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. bacterial helicobacter pylori can cause gastric cancer. although the data varies between different countries, overall about 1% to 3% of people infected with helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no h. pylori infection. h. pylori infection is very prevalent. as evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries. since 1% to 3% of infected individuals are likely to develop gastric cancer, h. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. infection by h. pylori causes no symptoms in about 80% of those infected. about 75% of individuals infected with h. pylori develop gastritis. thus, the usual consequence of h. pylori infection is chronic asymptomatic gastritis. because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. more than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed. the gastritis caused by h. pylori is accompanied by inflammation, characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines and reactive oxygen species/reactive nitrogen species (ros/rns). the substantial presence of ros/rns causes dna damage including 8-oxo-2'-deoxyguanosine (8-ohdg). if the infecting h. pylori carry the cytotoxic caga gene (present in about 60% of western isolates and a higher percentage of asian isolates), they can increase the level of 8-ohdg in gastric cells by 8-fold, while if the h. pylori do not carry the caga gene, the increase in 8-ohdg is about 4-fold. in addition to the oxidative dna damage 8-ohdg, h. pylori infection causes other characteristic dna damages including dna double-strand breaks. h. pylori also causes many epigenetic alterations linked to cancer development. these epigenetic alterations are due to h. pylori-induced methylation of cpg sites in promoters of genes and h. pylori-induced altered expression of multiple micrornas. as reviewed by santos and ribeiro h. pylori infection is associated with epigenetically reduced efficiency of the dna repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. in particular, raza et al. showed that expression of two dna repair proteins, ercc1 and pms2, was severely reduced once h. pylori infection had progressed to cause dyspepsia. dyspepsia occurs in about 20% of infected individuals. in addition, as reviewed by raza et al., human gastric infection with h. pylori causes epigenetically reduced protein expression of dna repair proteins mlh1, mgmt and mre11. reduced dna repair in the presence of increased dna damage increases carcinogenic mutations and is likely a significant cause of h. pylori carcinogenesis. viral main article: oncovirus 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 an 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 experience 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 thought 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. 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 main article: cancer stem cell 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 main article: somatic evolution in cancer 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