Developmental disability

From Wikipedia, the free encyclopedia

Developmental Disability
Specialty	Psychiatry

Developmental disability is a diverse group of chronic conditions that are due to mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, especially in "language, mobility, learning, self-help, and independent living". Developmental disabilities can be detected early on and persist throughout an individual's lifespan. Developmental disability that affects all areas of a child's development is sometimes referred to as global developmental delay.

Most common developmental disabilities:

• Down syndrome is a condition in which people are born with an extra copy of chromosome 21. Normally, a person is born with two copies of chromosome 21. However, if they are born with Down syndrome, they have an extra copy of this chromosome. This extra copy affects the development of the body and brain, causing physical and mental challenges for the individual.
• Fragile X syndrome (FXS) is thought to cause autism and intellectual disability, usually among boys.
• Pervasive developmental disorders (PDD) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges.
• Fetal alcohol spectrum disorders (FASD) are a group of conditions that can occur in a person whose mother drank alcohol during pregnancy.
• Cerebral palsy (CP) is a group of disorders that affect a person’s ability to move and maintain balance and posture. CP is the most common motor disability in childhood.
• Intellectual disability, also (sometimes proscriptively) known as mental retardation, is defined as an IQ below 70 along with limitations in adaptive functioning and onset before the age of 18 years.

Causes

The causes of developmental disabilities are varied and remain unknown in a large proportion of cases. Even in cases of known etiology the line between "cause" and "effect" is not always clear, leading to difficulty in categorizing causes.

Genetic factors have long been implicated in the causation of developmental disabilities. There is also a large environmental component to these conditions, and the relative contributions of nature versus nurture have been debated for decades.

Current theories on causation focus on genetic factors, and over 1,000 known genetic conditions include developmental disabilities as a symptom.

Developmental disabilities affect between 1 and 2% of the population in most western countries, although many government sources acknowledge that statistics are flawed in this area. The worldwide proportion of people with developmental disabilities is believed to be approximately 1.4%. It is twice as common in males as in females, and some researchers have found that the prevalence of mild developmental disabilities is likely to be higher in areas of poverty and deprivation, and among people of certain ethnicities.

Diagnosis and quantification

Developmental disabilities can be initially suspected when a child does not reach expected child development stages. Subsequently, a differential diagnosis may be used to diagnose an underlying disease, which may include a physical examination and genetic tests. 

The degree of disability can be quantified by assigning a developmental age to a person, which is age of the group into which test scores place the person. This, in turn, can be used to calculate a developmental quotient (DQ) as follows:

${\displaystyle DQ={\frac {Developmental\ age}{Chronological\ age}}*100}$

Associated issues

Physical health issues

There are many physical health factors associated with developmental disabilities. For some specific syndromes and diagnoses, these are inherent, such as poor heart function in people with Down syndrome. People with severe communication difficulties find it difficult to articulate their health needs, and without adequate support and education might not recognize ill health. Epilepsy, sensory problems (such as poor vision and hearing), obesity and poor dental health are over-represented in this population. Life expectancy among people with developmental disabilities as a group is estimated at 20 years below average, although this is improving with advancements in adaptive and medical technologies, and as people are leading healthier, more fulfilling lives, and some conditions (such as Freeman-Sheldon syndrome) do not impact life expectancy.

Mental health issues (dual diagnoses)

Mental health issues, and psychiatric illnesses, are more likely to occur in people with developmental disabilities than in the general population. A number of factors are attributed to the high incidence rate of dual diagnoses:

• The high likelihood of encountering traumatic events throughout their lifetime (such as abandonment by loved ones, abuse, bullying and harassment)
• The social and developmental restrictions placed upon people with developmental disabilities (such as lack of education, poverty, limited employment opportunities, limited opportunities for fulfilling relationships, boredom)
• Biological factors (such as brain injury, epilepsy, illicit and prescribed drug and alcohol misuse)
• Developmental factors (such as lack of understanding of social norms and appropriate behavior, inability of those around to allow/understand expressions of grief and other human emotions)
• External monitoring factor: all people with developmental disabilities that are in a federal- or state-funded residence require the resident to have some form of behavioral monitoring for each person with developmental disability at the residence. With this information psychological diagnoses are more easily given than with the general population that has less consistent monitoring.
• Access to health care providers: in the United States, all people with developmental disabilities that are in a federal- or state-funded residence require the residence to have annual visits to various health care providers. With consistent visits to health care providers more people with developmental disabilities are likely to receive appropriate treatment than the general population that is not required to visit various health care providers.

These problems are exacerbated by difficulties in diagnosis of mental health issues, and in appropriate treatment and medication, as for physical health issues.

Abuse and vulnerability

Abuse is a significant issue for people with developmental disabilities, and as a group they are regarded as vulnerable people in most jurisdictions. Common types of abuse include:

• Physical abuse (withholding food, hitting, punching, pushing, etc.);
• Neglect (withholding help when required, e.g., assistance with personal hygiene);
• Sexual abuse is associated with psychological disturbance. Sequeira, Howlin & Hollins found that sexual abuse was associated with increased rates of mental illness and behavioural problems, including symptoms of post-traumatic stress. Psychological reactions to abuse were similar to those observed in the general population, but with the addition of stereotypical behaviour. The more serious the abuse, the more severe the symptoms that were reported;
• Psychological or emotional abuse (verbal abuse, shaming and belittling);
• Constraint and restrictive practices (turning off an electric wheelchair so a person cannot move);
• Financial abuse (charging unnecessary fees, holding onto pensions, wages, etc.)
• Legal or civil abuse (restricted access to services);
• Systemic abuse (denied access to an appropriate service due to perceived support needs);
• Passive neglect (a caregiver's failure to provide adequate food, shelter).

Lack of education, lack of self-esteem and self-advocacy skills, lack of understanding of social norms and appropriate behavior and communication difficulties are strong contributing factors to the high incidence of abuse among this population.

In addition to abuse from people in positions of power, peer abuse is recognized as a significant, if misunderstood, problem. Rates of criminal offense among people with developmental disabilities are also disproportionately high, and it is widely acknowledged that criminal justice systems throughout the world are ill-equipped for the needs of people with developmental disabilities—as both perpetrators and victims of crime. Failings in care have been identified in one in eight deaths of people with learning difficulties under NHS England.

Challenging behavior

Some people with developmental disabilities exhibit challenging behavior, defined as "culturally abnormal behaviour(s) of such intensity, frequency or duration that the physical safety of the person or others is placed in serious jeopardy, or behaviour which is likely to seriously limit or deny access to the use of ordinary community facilities". Common types of challenging behavior include self-injurious behavior (such as hitting, headbutting, biting), aggressive behavior (such as hitting others, shouting, screaming, spitting, kicking, swearing, hairpulling), inappropriate sexualized behavior (such as public masturbation or groping), behavior directed at property (such as throwing objects and stealing) and stereotyped behaviors (such as repetitive rocking, echolalia or elective incontinence). Such behaviors can be assessed to suggest areas of further improvement, using assessment tools such as the Nisonger Child Behavior Rating Form (NCBRF). 

Challenging behavior in people with developmental disabilities may be caused by a number of factors, including biological (pain, medication, the need for sensory stimulation), social (boredom, seeking social interaction, the need for an element of control, lack of knowledge of community norms, insensitivity of staff and services to the person's wishes and needs), environmental (physical aspects such as noise and lighting, or gaining access to preferred objects or activities), psychological (feeling excluded, lonely, devalued, labelled, disempowered, living up to people's negative expectations) or simply a means of communication. A lot of the time, challenging behavior is learned and brings rewards and it is very often possible to teach people new behaviors to achieve the same aims. Challenging behavior in people with developmental disabilities can often be associated with specific mental health problems.

Experience and research suggests that what professionals call "challenging behavior" is often a reaction to the challenging environments that those providing services create around people with developmental disabilities. "Challenging behavior" in this context is a method of communicating dissatisfaction with the failure of those providing services to focus on what kind of life makes most sense to the person, and is often the only recourse a developmentally disabled person has against unsatisfactory services or treatment and the lack of opportunities made available to the person. This is especially the case where the services deliver lifestyles and ways of working that are centered on what suits the service provider and its staff, rather than what best suits the person. 

In general, behavioral interventions or what has been termed applied behavior analysis has been found to be effective in reducing specific challenging behavior. Recently, efforts have been placed on developing a developmental pathway model in the behavior analysis literature to prevent challenging behavior from occurring.

Societal attitudes

Throughout history, people with developmental disabilities have been viewed as incapable and incompetent in their capacity for decision-making and development. Until the Enlightenment in Europe, care and asylum was provided by families and the Church (in monasteries and other religious communities), focusing on the provision of basic physical needs such as food, shelter and clothing. Stereotypes such as the dimwitted village idiot, and potentially harmful characterizations (such as demonic possession for people with epilepsy) were prominent in social attitudes of the time.

Early in the twentieth century, the eugenics movement became popular throughout the world. This led to the forced sterilization and prohibition of marriage in most of the developed world and was later used by Hitler as rationale for the mass murder of mentally challenged individuals during the Holocaust. The eugenics movement was later thought to be seriously flawed and in violation of human rights and the practice of forced sterilization and prohibition from marriage was discontinued by most of the developed world by the mid 20th century. 

The movement towards individualism in the 18th and 19th centuries, and the opportunities afforded by the Industrial Revolution, led to housing and care using the asylum model. People were placed by, or removed from, their families (usually in infancy) and housed in large institutions (of up to 3,000 people, although some institutions were home to many more, such as the Philadelphia State Hospital in Pennsylvania which housed 7,000 people through the 1960s), many of which were self-sufficient through the labor of the residents. Some of these institutions provided a very basic level of education (such as differentiation between colors and basic word recognition and numeracy), but most continued to focus solely on the provision of basic needs. Conditions in such institutions varied widely, but the support provided was generally non-individualized, with aberrant behavior and low levels of economic productivity regarded as a burden to society. Heavy tranquilization and assembly line methods of support (such as "birdfeeding" and cattle herding) were the norm, and the medical model of disability prevailed. Services were provided based on the relative ease to the provider, not based on the human needs of the individual.

Ignoring the prevailing attitude, Civitans adopted service to the developmentally disabled as a major organizational emphasis in 1952. Their earliest efforts included workshops for special education teachers and daycamps for disabled children, all at a time when such training and programs were almost nonexistent. In the United States, the segregation of people with developmental disabilities wasn't widely questioned by academics or policy-makers until the 1969 publication of Wolf Wolfensberger's seminal work "The Origin and Nature of Our Institutional Models", drawing on some of the ideas proposed by SG Howe 100 years earlier. This book posited that society characterizes people with disabilities as deviant, sub-human and burdens of charity, resulting in the adoption of that "deviant" role. Wolfensberger argued that this dehumanization, and the segregated institutions that result from it, ignored the potential productive contributions that all people can make to society. He pushed for a shift in policy and practice that recognized the human needs of "retardates" and provided the same basic human rights as for the rest of the population. 

The publication of this book may be regarded as the first move towards the widespread adoption of the social model of disability in regard to these types of disabilities, and was the impetus for the development of government strategies for desegregation. Successful lawsuits against governments and an increasing awareness of human rights and self-advocacy also contributed to this process, resulting in the passing in the U.S. of the Civil Rights of Institutionalized Persons Act in 1980. 

From the 1960s to the present, most U.S. states have moved towards the elimination of segregated institutions. Along with the work of Wolfensberger and others including Gunnar and Rosemary Dybwad, a number of scandalous revelations around the horrific conditions within state institutions created public outrage that led to change to a more community-based method of providing services. By the mid-1970s, most governments had committed to de-institutionalization, and had started preparing for the wholesale movement of people into the general community, in line with the principles of normalization. In most countries, this was essentially complete by the late 1990s, although the debate over whether or not to close institutions persists in some states, including Massachusetts.

Individuals with developmental disabilities are not fully integrated into society. Person Centered Planning and Person Centered Approaches are seen as methods of addressing the continued labeling and exclusion of socially devalued people, such as people with a developmental disability label, encouraging a focus on the person as someone with capacities and gifts, as well as support needs.

Services and support

Today, support services are provided by government agencies, non-governmental organizations and by private sector providers. Support services address most aspects of life for people with developmental disabilities, and are usually theoretically based in community inclusion, using concepts such as social role valorization and increased self-determination (using models such as Person Centred Planning). Support services are funded through government block funding (paid directly to service providers by the government), through individualized funding packages (paid directly to the individual by the government, specifically for the purchase of services) or privately by the individual (although they may receive certain subsidies or discounts, paid by the government). There also are a number of non-profit agencies dedicated to enriching the lives of people living with developmental disabilities and erasing the barriers they have to being included in their community.

Education and training

Education and training opportunities for people with developmental disabilities have expanded greatly in recent times, with many governments mandating universal access to educational facilities, and more students moving out of special schools and into mainstream classrooms with support. 

Post-secondary education and vocational training is also increasing for people with these types of disabilities, although many programs offer only segregated "access" courses in areas such as literacy, numeracy and other basic skills. Legislation (such as the UK's Disability Discrimination Act 1995) requires educational institutions and training providers to make "reasonable adjustments" to curriculum and teaching methods in order to accommodate the learning needs of students with disabilities, wherever possible. There are also some vocational training centers that cater specifically to people with disabilities, providing the skills necessary to work in integrated settings, one of the largest being Dale Rogers Training Center in Oklahoma City.

At-home and community support

Many people with developmental disabilities live in the general community, either with family members, in supervised-group homes or in their own homes (that they rent or own, living alone or with flatmates). At-home and community supports range from one-to-one assistance from a support worker with identified aspects of daily living (such as budgeting, shopping or paying bills) to full 24-hour support (including assistance with household tasks, such as cooking and cleaning, and personal care such as showering, dressing and the administration of medication). The need for full 24-hour support is usually associated with difficulties recognizing safety issues (such as responding to a fire or using a telephone) or for people with potentially dangerous medical conditions (such as asthma or diabetes) who are unable to manage their conditions without assistance.

In the United States, a support worker is known as a Direct Support Professional (DSP). The DSP works in assisting the individual with their ADLs and also acts as an advocate for the individual with a developmental disability, in communicating their needs, self-expression and goals.

Supports of this type also include assistance to identify and undertake new hobbies or to access community services (such as education), learning appropriate behavior or recognition of community norms, or with relationships and expanding circles of friends. Most programs offering at-home and community support are designed with the goal of increasing the individual's independence, although it is recognized that people with more severe disabilities may never be able to achieve full independence in some areas of daily life.

Residential accommodation

Some people with developmental disabilities live in residential accommodation (also known as group homes) with other people with similar assessed needs. These homes are usually staffed around the clock, and usually house between 3 and 15 residents. The prevalence of this type of support is gradually decreasing, however, as residential accommodation is replaced by at-home and community support, which can offer increased choice and self-determination for individuals. Some U.S. states still provide institutional care, such as the Texas State Schools. The type of residential accommodation is usually determined by the level of developmental disability and mental health needs.

Employment support

Employment support usually consists of two types of support:

• Support to access or participate in integrated employment, in a workplace in the general community. This may include specific programs to increase the skills needed for successful employment (work preparation), one-to-one or small group support for on-the-job training, or one-to-one or small group support after a transition period (such as advocacy when dealing with an employer or a bullying colleague, or assistance to complete an application for a promotion).
• The provision of specific employment opportunities within segregated business services. Although these are designed as "transitional" services (teaching work skills needed to move into integrated employment), many people remain in such services for the duration of their working life. The types of work performed in business services include mailing and packaging services, cleaning, gardening and landscaping, timberwork, metal fabrication, farming and sewing.

Workers with developmental disabilities have historically been paid less for their labor than those in the general workforce, although this is gradually changing with government initiatives, the enforcement of anti-discrimination legislation and changes in perceptions of capability in the general community. 

In the United States, a variety of initiatives have been launched in the past decade to reduce unemployment among workers with disabilities—estimated by researchers at over 60%. Most of these initiatives are directed at employment in mainstream businesses. They include heightened placement efforts by the community agencies serving people with developmental disabilities, as well as by government agencies. 

Additionally, state-level initiatives are being launched to increase employment among workers with disabilities. In California, the state senate in 2009 created the Senate Select Committee on Autism and Related Disorders. The Committee has been examining additions to existing community employment services, and also new employment approaches. Committee member Lou Vismara, chairman of the MIND Institute at University of California, Davis, is pursuing the development of a planned community for persons with autism and related disorders in the Sacramento region. Another committee member, Michael Bernick, the former director of the state labor department, has established a program at the California state university system, starting at California State University East Bay, to support students with autism on the college level. Other Committee efforts include mutual support employment efforts, such as disability job networks, job boards, and identifying business lines that build on the strengths of persons with disabilities.

Day services

Non-vocational day services are usually known as day centers, and are traditionally segregated services offering training in life skills (such as meal preparation and basic literacy), center-based activities (such as crafts, games and music classes) and external activities (such as day trips). Some more progressive day centers also support people to access vocational training opportunities (such as college courses), and offer individualized outreach services (planning and undertaking activities with the individual, with support offered one-to-one or in small groups). 

Traditional day centers were based on the principles of occupational therapy, and were created as respite for family members caring for their loved ones with disabilities. This is slowly changing, however, as programs offered become more skills-based and focused on increasing independence.

Advocacy

Advocacy is a burgeoning support field for people with developmental disabilities. Advocacy groups now exist in most jurisdictions, working collaboratively with people with disabilities for systemic change (such as changes in policy and legislation) and for changes for individuals (such as claiming welfare benefits or when responding to abuse). Most advocacy groups also work to support people, throughout the world, to increase their capacity for self-advocacy, teaching the skills necessary for people to advocate for their own needs.

Other types of support

Other types of support for people with developmental disabilities may include

• therapeutic services, such as speech therapy, occupational therapy, physical therapy, massage, aromatherapy, art, dance/movement or music therapy;
• supported holidays;
• short-stay respite services (for people who live with family members or other unpaid carers);
• transport services, such as dial-a-ride or free bus passes;
• specialist behavior support services, such as high-security services for people with high-level, high-risk challenging behaviors;
• specialist relationships and sex education.

Programs are set up around the country in hopes to educate individuals with and without developmental disabilities. Studies have been done testing specific scenarios on how what is the most beneficial way to educate people. Interventions are a great way to educate people, but also the most time consuming. With the busy schedules that everybody has, it is found to be difficult to go about the intervention approach. Another scenario that was found to be not as beneficial, but more realistic in the time sense was Psychoeducational approach. They focus on informing people on what abuse is, how to spot abuse, and what to do when spotted. Individuals with developmental disabilities don't only need the support programs to keep them safe, but everybody in society needs to be aware of what is happening and how to help everybody prosper.

Mutagenesis

From Wikipedia, the free encyclopedia

 

Mutagenesis /mjuːtəˈdʒɛnɪsɪs/ is a process by which the genetic information of an organism is changed, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. In nature mutagenesis can lead to cancer and various heritable diseases, but it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

Background

DNA may be modified, either naturally or artificially, by a number of physical, chemical and biological agents, resulting in mutations. Hermann Muller found that "High temperatures" have the ability to mutate genes in the early 1920s, and in 1927, demonstrated a causal link to mutation upon experimenting with an x-ray machine and noting phylogenetic changes when irradiating fruit flies with relatively high dose of X-rays. Muller observed a number of chromosome rearrangements in his experiments, and suggested mutation as a cause of cancer. The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivity by Henri Becquerel. Muller's contemporary Lewis Stadler also showed the mutational effect of X-ray on barley in 1928, and ultraviolet (UV) radiation on maize in 1936. In 1940s, Charlotte Auerbach and J. M. Robson, found that mustard gas can also cause mutations in fruit flies.

While changes to the chromosome caused by X-ray and mustard gas were readily observable to the early researchers, other changes to the DNA induced by other mutagens were not so easily observable, and the mechanism may be complex and takes longer to unravel. For example, soot was suggested to be a cause of cancer as early as 1775, and coal tar was demonstrated to cause cancer in 1915. The chemicals involved in both were later shown to be polycyclic aromatic hydrocarbons (PAH). PAHs by themselves are not carcinogenic, and it was proposed in 1950 that the carcinogenic forms of PAHs are the oxides produced as metabolites from cellular processes. The metabolic process was identified in 1960s as catalysis by cytochrome P450 which produces reactive species that can interact with the DNA to form adducts,; the mechanism by which the PAH adducts give rise to mutation, however, is still under investigation. 

Mammalian nuclear DNA may sustain more than 60,000 damage episodes per cell per day, as listed with references in DNA damage (naturally occurring). If left uncorrected, these adducts, after misreplication past the damaged sites, can give rise to mutations. In nature, the mutations that arise may be beneficial or deleterious—this is the driving force of evolution. An organism may acquire new traits through genetic mutation, but mutation may also result in impaired function of the genes, and in severe cases, cause the death of the organism. In the laboratory, however, mutagenesis is a useful technique for generating mutations that allows the functions of genes and gene products to be examined in detail, producing proteins with improved characteristics or novel functions, as well as mutant strains with useful properties. Initially, the ability of radiation and chemical mutagens to cause mutation was exploited to generate random mutations, but later techniques were developed to introduce specific mutations. 

Humans on average naturally pass 60 new mutations to their children but fathers pass more mutations depending on their age, transmitting an average of two new mutations with every additional year of their age to the child.

Distinction between a mutation and DNA damage

DNA damage is an abnormal alteration in the structure of DNA that cannot, itself, be replicated when DNA replicates. In contrast, a mutation is a change in the nucleic acid sequence that can be replicated; hence, a mutation can be inherited from one generation to the next. Damage can occur from chemical addition (adduct), or structural disruption to a base of DNA (creating an abnormal nucleotide or nucleotide fragment), or a break in one or both DNA strands. When DNA containing damage is replicated, an incorrect base may be inserted in the new complementary strand as it is being synthesized. The incorrect insertion in the new strand will occur opposite the damaged site in the template strand, and this incorrect insertion can become a mutation (i.e. a changed base pair) in the next round of replication. Furthermore, double-strand breaks in DNA may be repaired by an inaccurate repair process, non-homologous end joining, which produces mutations. Mutations can ordinarily be avoided if accurate DNA repair systems recognize DNA damage and repair it prior to completion of the next round of replication. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in the 5 types of DNA repair processes.

Mechanisms

Mutagenesis may occur endogenously, for example, through spontaneous hydrolysis, or through normal cellular processes that can generate reactive oxygen species and DNA adducts, or through error in replication and repair. Mutagenesis may also arise as a result of the presence of environmental mutagens that induce changes to the DNA. The mechanism by which mutation arises varies according to the causative agent, the mutagen, involved. Most mutagens act either directly, or indirectly via mutagenic metabolites, on the DNA producing lesions. Some, however, may affect the replication or chromosomal partition mechanism, and other cellular processes.

Many chemical mutagens require biological activation to become mutagenic. An important group of enzymes involved in the generation of mutagenic metabolites is cytochrome P450. Other enzymes that may also produce mutagenic metabolites include glutathione S-transferase and microsomal epoxide hydrolase. Mutagens that are not mutagenic by themselves but require biological activation are called promutagens.

Many mutations arise as a result of problems caused by DNA lesions during replication, resulting in errors in replication. In bacteria, extensive damage to DNA due to mutagens results in single-stranded DNA gaps during replication. This induces the SOS response, an emergency repair process that is also error-prone, thereby generating mutations. In mammalian cells, stalling of replication at damaged sites induces a number of rescue mechanisms that help bypass DNA lesions, but which also may result in errors. The Y family of DNA polymerases specializes in DNA lesion bypass in a process termed translesion synthesis (TLS) whereby these lesion-bypass polymerases replace the stalled high-fidelity replicative DNA polymerase, transit the lesion and extend the DNA until the lesion has been passed so that normal replication can resume. These processes may be error-prone or error-free.

Spontaneous hydrolysis

DNA is not entirely stable in aqueous solution. Under physiological conditions the glycosidic bond may be hydrolyzed spontaneously and 10,000 purine sites in DNA are estimated to be depurinated each day in a cell. Numerous DNA repair pathways exist for DNA; however, if the apurinic site is not repaired, misincorporation of nucleotides may occur during replication. Adenine is preferentially incorporated by DNA polymerases in an apurinic site. 

Cytidine may also become deaminated to uridine at one five-hundredth of the rate of depurination and can result in G to A transition. Eukaryotic cells also contain 5-methylcytosine, thought to be involved in the control of gene transcription, which can become deaminated into thymine.

Modification of bases

Bases may be modified endogenously by normal cellular molecules. For example, DNA may be methylated by S-adenosylmethionine, and glycosylated by reducing sugars. 

Many compounds, such as PAHs, aromatic amines, aflatoxin and pyrrolizidine alkaloids, may form reactive oxygen species catalyzed by cytochrome P450. These metabolites form adducts with the DNA, which can cause errors in replication, and the bulky aromatic adducts may form stable intercalation between bases and block replication. The adducts may also induce conformational changes in the DNA. Some adducts may also result in the depurination of the DNA; it is, however, uncertain how significant such depurination as caused by the adducts is in generating mutation.

Alkylation and arylation of bases can cause errors in replication. Some alkylating agents such as N-Nitrosamines may require the catalytic reaction of cytochrome-P450 for the formation of a reactive alkyl cation. N⁷ and O⁶ of guanine and the N³ and N⁷ of adenine are most susceptible to attack. N⁷-guanine adducts form the bulk of DNA adducts, but they appear to be non-mutagenic. Alkylation at O⁶ of guanine, however, is harmful because excision repair of O⁶-adduct of guanine may be poor in some tissues such as the brain. The O⁶ methylation of guanine can result in G to A transition, while O⁴-methylthymine can be mispaired with guanine. The type of the mutation generated, however, may be dependent on the size and type of the adduct as well as the DNA sequence.

Ionizing radiation and reactive oxygen species often oxidize guanine to produce 8-oxoguanine.

DNA damage and spontaneous mutation

As noted above, the number of DNA damage episodes occurring in a mammalian cell per day is high (more than 60,000 per day). Frequent occurrence of DNA damage is likely a problem for all DNA- containing organisms, and the need to cope with DNA damage and minimize their deleterious effects is likely a fundamental problem for life.

Most spontaneous mutations likely arise from error-prone trans-lesion synthesis past a DNA damage site in the template strand during DNA replication. This process can overcome potentially lethal blockages, but at the cost of introducing inaccuracies in daughter DNA. The causal relationship of DNA damage to spontaneous mutation is illustrated by aerobically growing E. coli bacteria, in which 89% of spontaneously occurring base substitution mutations are caused by reactive oxygen species (ROS)-induced DNA damage. In yeast, more than 60% of spontaneous single-base pair substitutions and deletions are likely caused by trans-lesion synthesis.

An additional significant source of mutations in eukaryotes is the inaccurate DNA repair process non-homologous end joining, that is often employed in repair of double strand breaks.

In general, it appears that the main underlying cause of spontaneous mutation is error prone trans-lesion synthesis during DNA replication and that the error-prone non-homologous end joining repair pathway may also be an important contributor in eukaryotes.

Crosslinking

Some alkylating agents may produce crosslinking of DNA. Some natural occurring chemicals may also promote crosslinking, such as psoralens after activation by UV radiation, and nitrous acid. Interstrand cross-linking is more damaging as it blocks replication and transcription and can cause chromosomal breakages and rearrangements. Some crosslinkers such as cyclophosphamide, mitomycin C and cisplatin are used as anticancer chemotherapeutic because of their high degree of toxicity to proliferating cells.

Dimerization

UV radiation promotes the formation of a cyclobutyl ring between adjacent thymines, resulting in the formation of pyrimidine dimers. In human skin cells, thousands of dimers may be formed in a day due to normal exposure to sunlight. DNA polymerase η may help bypass these lesions in an error-free manner; however, individuals with defective DNA repair function, such as sufferers of xeroderma pigmentosum, are sensitive to sunlight and may be prone to skin cancer. 

Ethidium intercalated between two adenine-thymine base pairs.

Intercalation between bases

The planar structure of chemicals such as ethidium bromide and proflavine allows them to insert between bases in DNA. This insert causes the DNA's backbone to stretch and makes slippage in DNA during replication more likely to occur since the bonding between the strands is made less stable by the stretching. Forward slippage will result in deletion mutation, while reverse slippage will result in an insertion mutation. Also, the intercalation into DNA of anthracyclines such as daunorubicin and doxorubicin interferes with the functioning of the enzyme topoisomerase II, blocking replication as well as causing mitotic homologous recombination. 

Arrows indicates chromosomal breakages due to DNA damage

Backbone damage

Ionizing radiation may produce highly reactive free radicals that can break the bonds in the DNA. Double-stranded breakages are especially damaging and hard to repair, producing translocation and deletion of part of a chromosome. Alkylating agents like mustard gas may also cause breakages in the DNA backbone. Oxidative stress may also generate highly reactive oxygen species that can damage DNA. Incorrect repair of other damage induced by the highly reactive species can also lead to mutations.

Insertional mutagenesis

Transposons and viruses may insert DNA sequences into coding regions or functional elements of a gene and result in inactivation of the gene.

Effects on replication and DNA repair

While most mutagens produce effects that ultimately result in errors in replication, for example creating adducts that interfere with replication, some mutagens may directly affect the replication process or reduce its fidelity. Base analog such as 5-bromouracil may substitute for thymine in replication. Metals such as cadmium, chromium, and nickel can increase mutagenesis in a number of ways in addition to direct DNA damage, for example reducing the ability to repair errors, as well as producing epigenetic changes.

As a laboratory technique

Mutagenesis in the laboratory is an important technique whereby DNA mutations are deliberately engineered to produce mutant genes, proteins, or strains of organism. Various constituents of a gene, such as its control elements and its gene product, may be mutated so that the functioning of a gene or protein can be examined in detail. The mutation may also produce mutant proteins with interesting properties, or enhanced or novel functions that may be of commercial use. Mutant strains may also be produced that have practical application or allow the molecular basis of particular cell function to be investigated. 

Early methods of mutagenesis produced entirely random mutations; however, later methods of mutagenesis may produce site-specific mutation.

Types

• Directed mutagenesis
• Site-directed mutagenesis
• PCR mutagenesis
• Insertional mutagenesis
• Signature tagged mutagenesis
• Transposon mutagenesis
• Sequence saturation mutagenesis

Carcinogenesis

From Wikipedia, the free encyclopedia

Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

 

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

Variants of inherited genes may predispose individuals to cancer. In addition, environmental factors such as carcinogens and radiation cause mutations that may contribute to the development of cancer. Finally random mistakes in normal DNA replication may result in cancer causing mutations. A series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. On average, for example, 15 "driver mutations" and 60 "passenger" mutations are found in colon cancers. Mutations in genes that regulate cell division, apoptosis (cell death), and DNA repair may result in uncontrolled cell proliferation and cancer.

Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered. Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes. There are two broad categories of genes that are affected by these changes. Oncogenes may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Finally Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host. This process is also referred to as viral transformation.

Causes

Genetic and epigenetic

There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

DNA damage

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis

 

DNA damage is considered to be the primary cause of cancer. More than 60,000 new naturally occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes.

Additional DNA damages can arise from exposure to exogenous agents. As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer.

DNA damages can also be caused by endogenous (naturally occurring) agents. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis, and bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.

Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red.

A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer with some defects causing up to 100% lifetime chance of cancer (e.g. p53 mutations). Such germ line mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.

The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.

In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).

When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, more DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.

The somatic mutations and epigenetic alterations caused by DNA damages and deficiencies in DNA repair accumulate in field defects. Field defects are normal appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and improperly proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations. 

It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists; for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco, so the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA damaging agents that occur both at the highest concentrations and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene.

Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, 59 mutations shared by some, but not all regions, and 29 "private" mutations only present in one region.

The cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal stem cells may be the cells of origin in cancers. First, there exists a highly positive correlation (Spearman’s rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five orders of magnitude. This correlation means that if the normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. This strongly suggests that the main reason we have cancer is that our normal stem cells divide, which implies that cancer originates in normal stem cells. Second, statistics show that most human cancers are diagnosed in aged people. A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells cannot keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.

Contribution of field defects

Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.

 

The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise.

Field defects have been identified in association with cancers and are important in progression to cancer. However, it was pointed out by Rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" More than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.

In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated (in the diagram below the photo) by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon.

If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm.

In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect. 

Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size.

Genome instability

Cancers are known to exhibit genome instability or a mutator phenotype. The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA. Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations. However, the average number of DNA sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (where melanomas have a higher exome mutation frequency) the total number of DNA sequence mutations is about 80,000. These high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in DNA repair. Large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) are found to frequently have epigenetic defects in 2 or 3 DNA repair proteins (ERCC1, XPF and/or PMS2) in the entire area of the field defect. When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of mutation and/or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage.

Non-mainstream theories

There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made. 

Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy (numerical and structural abnormalities in chromosomes) rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species. This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis) and the accumulation of reactive oxygen species leading to oxidative stress (oxidative stress theory of cancer). All these theories of carcinogenesis may be complementary rather than contradictory. Aberrant DNA methylation patterns – hypermethylation and hypomethylation compared to normal tissue – have been associated with a large number of human malignancies.

A number of authors have questioned the assumption that cancers result from sequential random mutations as oversimplistic, suggesting instead that cancer results from a failure of the body to inhibit an innate, programmed proliferative tendency. A related theory developed by astrobiologists suggests that cancer is an atavism, an evolutionary throwback to an earlier form of multicellular life. The genes responsible for uncontrolled cell growth and cooperation between cancer cells are very similar to those that enabled the first multicellular life forms to group together and flourish. These genes still exist within the genome of more complex metazoans, such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body. Instead they possess a fixed number of primitive genes that are progressively activated, giving them finite variability. Another evolutionary theory puts the roots of cancer back to the origin of the eukarote (nucleated) cell by massive horizontal gene transfer, when the genomes of infecting viruses were cleaved (and thereby attenuated) by the host, but their fragments integrated into the host genome as immune protection. Cancer now originates when a rare somatic mutation recombines such fragments into a functional driver of cell proliferation.

Cancer cell biology

Tissue can be organized in a continuous spectrum from normal to cancer.

 

Often, the multiple genetic changes that result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Clonal evolution

Just like a population of animals undergoes evolution, an unchecked population of cells also can undergo evolution. This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant.

Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed. This is exactly how pathogens such as MRSA can become antibiotic-resistant (or how HIV can become drug-resistant), and the same reason why crop blights and pests can become pesticide-resistant. This evolution is why cancer recurrences will have cells that have acquired cancer-drug resistance (or in some cases, resistance to radiation from radiotherapy).

Biological properties of cancer cells

In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:

• Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
• Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
• Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
• Loss of capacity for senescence, leading to limitless replicative potential (immortality)
• Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
• Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
• Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).

The completion of these multiple steps would be a very rare event without :

• Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.

These biological changes are classical in carcinomas; other malignant tumors may not need to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells.

Cancer as a defect in cell interactions

Normally, once a tissue is injured or infected, damaged cells elicit inflammation, by stimulating specific patterns of enzyme activity and cytokine gene expression on surrounding cells. Discrete clusters of molecules are secreted, which act as mediators, inducing the activity of subsequent cascades of biochemical changes. Each cytokine binds to specific receptors on various cell types, and each cell type responds differently by altering the activity of intracellular signal transduction pathways, depending on the receptors that the cell expresses and the signaling molecules present inside the cell. Collectively, this reprogramming process induces a stepwise change in cell phenotypes, which will ultimately lead to restoration of tissue function and toward regaining essential structural integrity. A tissue can thereby heal, depending on the productive communication between the cells present at the site of damage, and the immune system. Key factor in healing is the regulation of cytokine gene expression, which enables complementary groups of cells to respond to inflammatory mediators in a manner that gradually produces essential changes in tissue physiology. Cancer cells have either permanent (genetic) or reversible (epigenetic) changes on their genome, which partly inhibit their communication with surrounding cells and with the immune system. Cancer cells do not communicate with their tissue microenvironment in a manner that protects tissue integrity; instead, the movement and the survival of cancer cells become possible in locations where they can impair tissue function. Cancer cells survive by rewiring signal pathways that normally protect the tissue from the immune system. 

One example for rewiring of tissue function in cancer is the activity of transcription factor NF-κB. NF-κB activates the expression of numerous genes that are involved in the transition between inflammation and regeneration, which encode cytokines, adhesion factors, and other molecules that can change cell fate. This reprogramming of cellular phenotypes normally allows the development of a fully functional intact tissue. NF-κB activity is tightly controlled by multiple proteins, which collectively ensure that only discrete clusters of genes are induced by NF-κB in a given cell and at a given time. This tight regulation of signal exchange between cells, protects the tissue from excessive inflammation, and ensures that different cell types would gradually acquire complementary functions, and specific positions. Failure of this mutual regulation between genetic reprogramming and cell interactions allows cancer cells to give rise to metastasis. Cancer cells respond aberrantly to cytokines, and activate signal cascades that can protect them from the immune system.

In fishes

The role of iodine in marine fishes (rich in iodine) and freshwater fishes (iodine-deficient) is not completely understood, but it has been reported that freshwater fishes are more susceptible to infectious and, in particular, neoplastic and atherosclerotic diseases, of marine fishes. Marine elasmobranch fishes such as sharks, stingrays etc. are much less affected by cancer than freshwater fishes, and therefore have stimulated medical research to better understand carcinogenesis so it can be useful in other animals and especially in humans.

Mechanisms

In order for cells to start dividing uncontrollably, genes that regulate cell growth must be dysregulated. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. This concept is sometimes termed "oncoevolution." Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. But the uncontrolled cell division that characterizes cancer also requires that the dividing cell duplicates all its cellular components to create two daughter cells. The activation of anaerobic glycolysis (the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes, provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis.

Oncogenes

Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to affect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. 

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive. 

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also, when ligated to a stimulating control element, it could induce cancers in cell line cultures.

Proto-oncogenes

Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. 

Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance of dividing excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. It is important to note that a gene possessing a growth-promoting role may increase the carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. This condition also includes the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes identification of the stage and type of cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies.

Tumor suppressor genes

Many tumor suppressor genes effect signal transduction pathways that regulate apoptosis, also known as "programmed cell death".

 

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis. 

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.

Multiple mutations

Multiple mutations in cancer cells

 

In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first hypothesised by the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop. 

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Rb mutations develop retinoblastoma. In similar fashion, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. 

A new idea announced in 2011 is an extreme version of multiple mutations, called chromothripsis by its proponents. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering probably takes place when the chromosomes are compacted during normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations.

Non-mutagenic carcinogens

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.

Role of infections

Bacterial

Heliobacter pylori is known to cause MALT lymphoma. Other types of bacteria have been implicated in other cancers.

Viral

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection. The mode of virally induced tumors can be divided into two, acutely transforming or slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene. 

Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost. 

Depending on their location, cells can be damaged through radiation, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage. Cells often die if they are damaged, through failure of a vital process or the immune system, however sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low.

When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will suffer knock-outs. 

This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working. 

One concern is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth.

Helminthiasis

Certain parasitic worms are known to be carcinogenic. These include:

• Clonorchis sinensis (the organism causing Clonorchiasis) and Opisthorchis viverrini (causing Opisthorchiasis) are associated with cholangiocarcinoma.
• Schistosoma species (the organisms causing Schistosomiasis) is associated with bladder cancer.

Epigenetics

Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell. 

Epimutations include methylations or demethylations of the CpG islands of the promoter regions of genes, which result in repression or de-repression, respectively of gene expression. Epimutations can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer. In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as HMGA2.^[103] A further source of epimutation is due to increased or decreased expression of microRNAs (miRNAs). For example, extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers.

Cancer stem cells

A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control. Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells. The cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis. The cancer stem cell hypothesis has been a proposed mechanism that contributes to tumour heterogeneity.

Clonal evolution

While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment. Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment. Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution. Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertarial and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulative group dynamics.