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Cancer   i /ˈk æ n s ər /, known medically as a malignant neoplasm, is a broad group of diseases involvingunregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, andinvade nearby parts of the body. The cancer may alsospread to more distant parts of the body throughthe lymphatic system or bloodstream. Not all tumors are cancerous; benign tumors do not invadeneighboring tissues and do not spread throughout the body. There are over 200 different knowncancers that affect humans.[1]

The causes of cancer are diverse, complex, and only partially understood. Many things are known toincrease the risk of cancer, including tobacco use, dietary factors, certaininfections, exposure

to radiation, lack of physical activity, obesity, and environmental pollutants.[2] These factors can directlydamage genes or combine with existing genetic faults within cells to cause cancerous mutations.[3] Approximately 5–10% of cancers can be traced directly to inherited genetic defects. [4] Many cancerscould be prevented by not smoking, eating more vegetables, fruits and whole grains, eating less meatand refined carbohydrates, maintaining a healthy weight, exercising, minimizing sunlight exposure, andbeing vaccinated against some infectious diseases.[2][5]

Cancer can be detected in a number of ways, including the presence of certain signs andsymptoms, screening tests, or medical imaging. Once a possible cancer is detected it is diagnosedby microscopic examination of a tissue sample. Cancer is usually treated withchemotherapy, radiationtherapy and surgery. The chances of surviving the disease vary greatly by the type and location of thecancer and the extent of disease at the start of treatment. While cancer can affect people of all ages,

and a few types of cancer are more common in children, the risk of developing cancer generallyincreases with age. In 2007, cancer caused about 13% of all human deaths worldwide (7.9 million).Rates are rising as more people live to an old age and as mass lifestyle changes occur in thedeveloping world.[6]

Contents[show]

Definitions

There is no one definition that describes all cancers. They are a large family of diseases which form asubset of neoplasms, which show some features that suggest of  malignancy. A neoplasm or tumor is agroup of cells that have undergone unregualated growth, and will often form a mass or lump, but maybe distributed diffusely.[7][8]

Six characteristics of malignancies have been proposed: sustaining proliferative signaling, evadinggrowth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, andactivating invasion and metastasis.[9] The progression from normal cells to cells that can form adiscernible mass to outright cancer involves multiple steps. [9][10]

Signs and symptoms

Main article: Cancer signs and symptoms

Symptoms of cancer metastasis depend on the location of the tumor.When cancer begins it invariably produces no symptoms with signs and symptoms only appearing asthe mass continues to grow or ulcerates. The findings that result depend on the type and location of the

cancer. Few symptoms are specific, with many of them also frequently occurring in individuals whohave other conditions. Cancer is the new "great imitator ". Thus it is not uncommon for peoplediagnosed with cancer to have been treated for other diseases to which it was assumed their symptoms were due.[11]

Local effectsLocal symptoms may occur due to the mass of the tumor or its ulceration. For example, mass effectsfrom lung cancer can cause blockage of the bronchus resulting in cough or pneumonia; esophagealcancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and colorectalcancer may lead to narrowing or blockages in the bowel, resulting in changes in bowel habits. Massesin breasts or testicles may be easily felt.Ulceration can cause bleeding which, if it occurs in the lung,will lead to coughing up blood, in the bowels to anemia or rectal bleeding, in the bladder to blood in the

urine, and in the uterus to vaginal bleeding. Although localized pain may occur in advanced cancer, theinitial swelling is usually painless. Some cancers can cause build up of fluid within the chest or abdomen.[11]

Systemic symptoms

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General symptoms occur due to distant effects of the cancer that are not related to direct or metastaticspread. These may include: unintentional weight loss, fever , being excessively tired, and changes tothe skin.[12] Hodgkin disease, leukemias, and cancers of the liver or kidney can cause a persistent fever of unknown origin.[11]

Specific constellations of systemic symptoms, termed paraneoplastic phenomena, may occur withsome cancers. Examples include the appearance of myastheniagravis in thymoma and clubbing in lung cancer .[11]

Metastasis

Main article: MetastasisSymptoms of metastasis are due to the spread of cancer to other locations in the body. They caninclude enlarged lymph nodes (which can be felt or sometimes seen under the skin and are typicallyhard), hepatomegaly (enlarged liver) or splenomegaly (enlarged spleen) which can be felt inthe abdomen, pain or fracture of affected bones, and neurological symptoms.[11] Most cancer deathsare due to cancer that has spread from its primary site to other organs (metastasized). [13]

Causes

Cancers are primarily an environmental disease with 90–95% of cases attributed to environmentalfactors and 5–10% due to genetics. [2]  Environmental  , as used by cancer researchers, means any causethat is not inherited genetically, not merely pollution.[14] Common environmental factors that contributeto cancer death include tobacco (25–30%), diet and obesity (30–35%), infections (15–

20%),radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity,and environmental pollutants.[2]

It is nearly impossible to prove what caused a cancer in any individual, because most cancers havemultiple possible causes. For example, if a person who uses tobacco heavily develops lung cancer,then it was probably caused by the tobacco use, but since everyone has a small chance of developinglung cancer as a result of air pollution or radiation, then there is a small chance that the cancer developed because of air pollution or radiation.ChemicalsFurther information: Alcohol and cancer  and Smoking and cancer 

The incidence of lung cancer is highly correlated with smoking.Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis.Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers areknown as carcinogens. Particular substances have been linked to specific types of cancer. Tobaccosmoking is associated with many forms of cancer,[15] and causes 90% of lung cancer .[16]

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an exampleof a chemical carcinogen that is not a mutagen. [17] In Western Europe 10% of cancers in males and 3%of cancers in females are attributed to alcohol.[18]

Decades of research has demonstrated the link between tobacco use and cancer in thelung, larynx,head, neck, stomach, bladder, kidney, esophagus and pancreas.[19] Tobacco smoke contains over fiftyknown carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[20] Tobacco is

responsible for about one in three of all cancer deaths in the developed world,

[15]

and about one in fiveworldwide.[20] Lung cancer death rates in the United States have mirrored smoking patterns, withincreases in smoking followed by dramatic increases in lung cancer death rates and, more recently,decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in mensince 1990.[21][22] However, the numbers of smokers worldwide is still rising, leading to what someorganizations have described as the tobacco epidemic .[23]

Cancer related to one's occupation is believed to represent between 2–20% of all cases. [24] Every year,at least 200,000 people die worldwide from cancer related to their workplace. [25] Most cancer deathscaused by occupational risk factors occur in the developed world. [25] It is estimated that approximately20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable tooccupation.[26] Millions of workers run the risk of developing cancers such as lung

cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia fromexposure to benzene at their workplaces.[25]

Diet and exerciseDiet, physical inactivity, and obesity are related to approximately 30–35% of cancer deaths.[2][27] In theUnited States excess body weight is associated with the development of many types of cancer and is a

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factor in 14–20% of all cancer deaths. [27] Physical inactivity is believed to contribute to cancer risk notonly through its effect on body weight but also through negative effects on immunesystem and endocrine system.[27] More than half of the effect from diet is due to overnutrition rather than from eating too little healthy foods.Diets that are low in vegetables, fruits and whole grains, and high in processed or red meats are linkedwith a number of cancers.[27] A high-salt diet is linked to gastric cancer , aflatoxin B1, a frequent foodcontaminate, with liver cancer, and Betel nut chewing with oral cancer.[28] This may partly explaindifferences in cancer incidence in different countries. For example, gastric cancer is more common in

Japan due to its high-salt diet [29] and colon cancer is more common in the United States. Immigrantsdevelop the risk of their new country, often within one generation, suggesting a substantial link betweendiet and cancer.[30]

InfectionMain article: Infectious causes of cancer Worldwide approximately 18% of cancer deaths are related to infectious diseases.[2] This proportionvaries in different regions of the world from a high of 25% in Africa to less than 10% in the developedworld.[2] Viruses are the usual infectious agents that cause cancer but bacteria and parasites may alsohave an effect.

 A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervicalcarcinoma), Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal

carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusionlymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cellleukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seenin Helicobacter pylori-induced gastric carcinoma.[31] Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder ) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[32]

RadiationMain article: radiation-induced cancer Up to 10% of invasive cancers are related to radiation exposure, including both ionizingradiation and non-ionizing ultraviolet radiation.[2] Additionally, the vast majority of non-invasive cancersare non-melanoma skin cancers caused by non-ionizing ultraviolet radiation.

Sources of ionizing radiation include medical imaging, and radon gas. Radiation can cause cancer inmost parts of the body, in all animals, and at any age, although radiation-induced solid tumors usuallytake 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear.[33] Some people, such as those with nevoidbasal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developingcancer from radiation exposure.[33]Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect. [33] Ionizingradiation is not a particularly strong mutagen.[33] Residential exposure to radon gas, for example, hassimilar cancer risks as passive smoking.[33] Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development. [33] Radiation is amore potent source of cancer when it is combined with other cancer-causing agents, such as radon

gas exposure plus smoking tobacco.[33]

Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells randomly. If it happens to strike achromosome, it can break the chromosome, result in an abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other types of chromosomeabnormalities.[33] Major damage normally results in the cell dying, but smaller damage may leave astable, partly functional cell that may be capable of proliferating and developing into cancer, especiallyif tumor suppressor genes were damaged by the radiation.[33]Three independent stages appear to beinvolved in the creation of cancer with ionizing radiation: morphological changes to the cell,acquiring cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptationsthat favor formation of a tumor.[33]Even if the radiation particle does not strike the DNA directly, it

triggers responses from cells that indirectly increase the likelihood of mutations.[33]

Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing radiationmay be used to treat other cancers, but this may, in some cases, induce a second form of cancer. [33] Itis also used in some kinds of medical imaging. One report estimates that approximately 29,000 futurecancers could be related to the approximately 70 million CT scans performed in the US in 2007.[34] It is

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estimated that 0.4% of cancers in 2007 in the United States are due to CTs performed in the past andthat this may increase to as high as 1.5–2% with rates of CT usage during this same time period. [35]

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skinmalignancies.[36] Clear evidence establishes ultraviolet radiation, especially the non-ionizing mediumwave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.[36]

Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health

Organization's International Agency for Research on Cancer .[37] However, studies have not found aconsistent link between cell phone radiation and cancer risk.[38]

HeredityMain article: Cancer syndromeThe vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are primarilycaused by an inherited genetic defect. Less than 0.3% of the population are carriers of a geneticmutation which has a large effect on cancer risk and these cause less than 3–10% of all cancer.[39] Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 witha more than 75% risk of breast cancer and ovarian cancer ,[39] and hereditary nonpolyposis colorectalcancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer ,[40] among others.

Physical agentsSome substances cause cancer primarily through their physical, rather than chemical, effects on cells.[41]

 A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fiberswhich are a major cause of mesothelioma, which is a cancer of the serous membrane, usually theserous membrane surrounding the lungs.[41] Other substances in this category, including both naturallyoccurring and synthetic asbestos-like fibers such as wollastonite, attapulgite, glass wool, androck wool,are believed to have similar effects.[41]

Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz,cristobalite, and tridymite).[41]

Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and

require years of exposure to develop cancer.[41]

Physical trauma resulting in cancer is relatively rare. [42] Claims that breaking bones resulted in bonecancer, for example, have never been proven. [42] Similarly, physical trauma is not accepted as a causefor cervical cancer, breast cancer, or brain cancer.[42]

One accepted source is frequent, long-term application of hot objects to the body. It is possible thatrepeated burns on the same part of the body, such as those produced by kanger and kairo heaters(charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are alsopresent.[42] Frequently drinking scalding hot tea may produce esophageal cancer. [42]

Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during theprocess of repairing the trauma, rather than the cancer being caused directly by the trauma.[42] However, repeated injuries to the same tissues might promote excessive cell proliferation, which

could then increase the odds of a cancerous mutation. There is no evidence that inflammation itself causes cancer.[42]

HormonesSome hormones play a role in the development of cancer by promoting cell proliferation.[43] Insulin-likegrowth factors and their binding proteins play a key role in cancer cell proliferation, differentiation andapoptosis, suggesting possible involvement in carcinogenesis. [44]

Hormones are important agents in sex-related cancers such as cancer of the breast, endometrium,prostate, ovary, and testis, and also of thyroid cancer and bone cancer .[43] For example, the daughtersof women who have breast cancer have significantly higher levels of estrogen and progesterone thanthe daughters of women without breast cancer. These higher hormone levels may explain why thesewomen have higher risk of breast cancer, even in the absence of a breast-cancer gene. [43] Similarly,

men of African ancestry have significantly higher levels of testosterone than men of European ancestry,and have a correspondingly much higher level of prostate cancer. [43] Men of Asian ancestry, with thelowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostatecancer.[43]

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Other factors are also relevant: obese people have higher levels of some hormones associated withcancer and a higher rate of those cancers. [43] Women who take hormone replacement therapy have ahigher risk of developing cancers associated with those hormones.[43] On the other hand, people whoexercise far more than average have lower levels of these hormones, and lower risk of cancer.[43] Osteosarcoma may be promoted by growth hormones.[43] Some treatments and preventionapproaches leverage this cause by artificially reducing hormone levels, and thus discouraginghormone-sensitive cancers.[43]

Other 

Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors,cancer is generally not atransmissible disease. The main reason for this is tissue graft rejection causedby MHC incompatibility.[45] In humans and other vertebrates, the immune system uses MHC antigens todifferentiate between "self" and "non-self" cells because these antigens are different from person toperson. When non-self antigens are encountered, the immune system reacts against the appropriatecell. Such reactions may protect against tumour cell engraftment by eliminating implanted cells. In theUnited States, approximately 3,500 pregnant women have a malignancy annually, and transplacentaltransmission of acute leukemia, lymphoma, melanoma and carcinomafrom mother to fetus has beenobserved.[45] The development of donor-derived tumors from organ transplants is exceedingly rare. Themain cause of organ transplant associated tumors seems to be malignant melanoma, that wasundetected at the time of organ harvest. [46] Job stress does not appear to be a significant factor at least

in lung, colorectal, breast and prostate cancers.[47]

Pathophysiology

Main article: Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Genetic alterationsCancer is fundamentally a disease of tissue growth regulation failure. In order for a normal celltotransform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.[48]

The affected genes are divided into two broad categories. Oncogenes are genes which promote cell

growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival.Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes.Typically, changes in many genes are required to transform a normal cell into a cancer cell. [49]

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of anentirechromosome can occur through errors in mitosis. More common are mutations, which arechanges in the nucleotide sequence of genomic DNA.Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomicamplificationoccurs when a cell gains many copies (often 20 or more) of a small chromosomal locus,usually containing one or more oncogenes and adjacent genetic material. Translocation occurs whentwo 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 inthepromoter region of a gene and affect its expression, or may occur in the gene's codingsequence and alter the function or stability of its protein product. Disruption of a single gene may alsoresult fromintegration of genomic material from a DNA virus or retrovirus, and resulting in theexpression of viral oncogenes in the affected cell and its descendants.Replication of the enormous amount of data contained within the DNA of living cellswill probabilisticallyresult in some errors (mutations). Complex error correction and prevention is builtinto the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell

can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail,then the mutations will survive and be passed along to daughter cells.Some environments make errors more likely to arise and propagate. Such environments can includethe presence of disruptive substances called carcinogens, repeated physical injury, heat, ionisingradiation, or hypoxia.[50]

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The errors which cause cancer are self-amplifying and compounding , for example:•  A mutation in the error-correcting machinery of a cell might cause that cell and its children to

accumulate errors more rapidly.•  A further mutation in an oncogene might cause the cell to reproduce more rapidly and more

frequently than its normal counterparts.•  A further mutation may cause loss of a tumour suppressor gene, disrupting the apoptosis

signalling pathway and resulting in the cell becoming immortal.•  A further mutation in signaling machinery of the cell might send error-causing signals to nearby

cells.The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, whichcompound into more severe errors, each progressively allowing the cell to escape the controls that limitnormal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, wherethe driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution drives progression towards moreinvasive stages.[51]

Epigenetic alterationsClassically, cancer has been viewed as a set of diseases that are driven by progressive geneticabnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomalabnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.[52]

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve achange in the nucleotide sequence. Examples of such modifications are changes in DNAmethylation (hypermethylation and hypomethylation) and histone modification [53] and changes inchromosomal architecture (caused by inappropriate expression of proteins suchas HMGA2 or HMGA1).[54] Each of these epigenetic alterations serves to regulate gene expressionwithout altering the underlying DNA sequence. These changes may remain through cell divisions, lastfor multiple generations, and can be considered to be epimutations (equivalent to mutations).Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger andDiederich[55] listed protein coding genes that were frequently altered in their methylation in associationwith colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of thehypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were

hypermethylated in more than 50% of colon cancers.While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNArepair genes, causing reduced expression of DNA repair proteins, may be of particular importance.Such alterations are thought to occur early in progression to cancer and to be a likely cause of the geneticinstability characteristic of cancers.[56][57][58][59]

Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure atthe 4th level from the top. (In the figure, red wording indicates the central role of DNA damage anddefects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain incells at a higher than usual level (5th level from the top in figure), and these excess damages causeincreased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation ratesincrease substantially in cells defective in DNA mismatch repair [60]  [61]  or in homologous

recombinational repair (HRR).[62] Chromosomal rearrangements and aneuploidy also increase in HRRdefective cells.[63]

Higher levels of DNA damage not only cause increased mutation (right side of figure), but also causeincreased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages,incompletely cleared sites of repair can cause epigenetic gene silencing. [64][65]

Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder ) have an increased risk of cancer, with some defects causing up to a 100% lifetimechance of cancer (e.g. p53 mutations).[66] Germ line DNA repair mutations are noted in a box on the leftside of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, suchgermline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1

percent of cancers.[67]

In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expressionof DNA repair genes. This is indicated in the figure at the 3rd level from the top. For example, when113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA

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repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMTpromoter region (an epigenetic alteration).[68] Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[69][70][71][72][73]

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103cases PMS2 expression was deficient because its pairing partner MLH1was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[74] In the other 10 cases, loss of PMS2

expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[75]

In further examples, tabulated in the article Epigenetics, epigenetic defects were found at frequenciesof between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF,MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM in cancers including those in breast,ovarian, colorectal, and head and neck. In particular, two or more epigenetic deficiencies in expressionof ERCC1, XPF and/or PMS2 occurred simultaneously in the majority of the 49 colon cancersevaluated by Facista et al. [76]

Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction inexpression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. For 

example, one group of studies shows that arsenic inhibits the DNA repair genes PARP,XRCC1, LigaseIII, Ligase IV, DNA POLB, XRCC4, DNAPKCS, TOPO2B, OGG1, ERCC1, XPF, XPB, XPC, XPE andP53.[77][78][79][80][81][82] Another group of studies shows that cadmium inhibits the DNA repair genes MSH2, ERCC1, XRCC1, OGG1,MSH6, DNA-PK, XPD and XPC.[83][84][85][86][87]

Cancers usually arise from an assemblage of mutations and epimutations that confer a selectiveadvantage leading to clonal expansion (see Field defects in progression to cancer ). Mutations,however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breastor 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. [88] Colon cancers were also found tohave an average of 17 duplicated segments of chromosomes, 28 deleted segments of chromosomes

and up to 10 translocations.[89]

However, by comparison, epigenetic alterations appear to be morefrequent in colon cancers. There are large numbers of hypermethylated genes in colon cancer, asdiscussed above.[55]

In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAscalled microRNAs (or miRNAs). MiRNAs do not code for proteins, but can “target” protein-coding genesand reduce their expression. For instance, epigenetic increase in CpG island methylation of the DNAsequence encoding miR-137 reduces its expression and is a frequent early epigenetic event incolorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearingcolonic mucosa adjacent to the cancers. Silencing of miR-137 can affect expression of over 400 genes,the targets of this miRNA. [90] Changes in the level of miR-137 expression cause altered mRNAexpression of the target genes by 2 to 20-fold and corresponding, though often smaller, changes in

expression of the protein products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more frequently epigenetically altered in colonic field defects and in the coloncancers that arise from them. These include miR-124a, miR-34b/c and miR-342 which are silenced byCpG island methylation of their encoding DNA sequences in primary tumors at rates of 99%, 93% and86%, respectively, and in the adjacent normal appearing mucosa at rates of 59%, 26% and 56%,respectively.[91][92] Thus, epigenetic alterations are a major source of changes in gene expression,important in cancer.

 As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth,when the genes which regulate cell growth and differentiation are altered. It has become clear thatthese alterations are caused by both DNA sequence mutation inoncogenes and tumor suppressor genes as well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair 

genes, in particular, likely cause an increased frequency of mutations, some of which then occur inoncogenes and tumor suppressor genes.Diagnosis

Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these lead to a definitive diagnosis, which requires the examination of a

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tissue sample by a pathologist. People with suspected cancer are investigated with medical tests.These commonly include blood tests, X-rays, CT scansand endoscopy.Most people are distressed to learn that they have cancer. They may become extremely anxious anddepressed. The risk of suicide in people with cancer is approximately double the normal risk.[93]

ClassificationFurther information: List of cancer types and List of oncology-related termsCancers are classified by the type of cell that the tumor cells resemble and is therefore presumed to bethe origin of the tumor. These types include:• Carcinoma: Cancers derived from epithelial cells. This group includes many of the most

common cancers, particularly in the aged, and include nearly all those developing inthe breast, prostate, lung, pancreas, and colon.

• Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), each of which

develop from cells originating inmesenchymal cells outside the bone marrow.• Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming)

cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively.Leukemia is the most common type of cancer in children accounting for about 30%.[94]

• Germ cell tumor : Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma anddysgerminoma, respectively).

• Blastoma: Cancers derived from immature "precursor" cells or embryonic tissue. Blastomas are

more common in children than in older adults.Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, cancers of theliver parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a malignancyarising from primitive liver precursor cells is called a hepatoblastoma, and a cancer arising from fatcells is called aliposarcoma. For some common cancers, the English organ name is used. For example,the most common type of breast cancer is called ductal carcinoma of the breast . Here, theadjective ductal refers to the appearance of the cancer under the microscope, which suggests that ithas originated in the milk ducts.Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as theroot. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of 

this frequently occurring benign tumor in the uterus is fibroid ). Confusingly, some types of cancer usethe -noma suffix, examples including melanoma and seminoma.Some types of cancer are named for the size and shape of the cells under a microscope, such as giantcell carcinoma, spindle cell carcinoma, and small-cell carcinoma.PathologyThe tissue diagnosis given by the pathologist indicates the type of cell that is proliferating,its histological grade, genetic abnormalities, and other features of the tumor. Together, this informationis useful to evaluate the prognosis of the patient and to choose the besttreatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist mayperform on the tissue specimen. These tests may provide information about the molecular changes(such as mutations, fusion genes, and numerical chromosomechanges) that has happened in the

cancer cells, and may thus also indicate the future behavior of the cancer (prognosis) and besttreatment.Prevention

Cancer prevention is defined as active measures to decrease the risk of cancer. [95] The vast majority of cancer cases are due to environmental risk factors, and many, but not all, of these environmentalfactors are controllable lifestyle choices. Thus, cancer is considered a largely preventable disease.[96] Greater than 30% of cancer deaths could be prevented by avoiding risk factorsincluding:tobacco, overweight / obesity, an insufficient diet, physical inactivity, alcohol, sexuallytransmitted infections, and air pollution.[97] Not all environmental causes are controllable, such asnaturally occurring background radiation, and other cases of cancer are caused through hereditarygenetic disorders, and thus it is not possible to prevent all cases of cancer.

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