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Malignant transformation

From Wikipedia, the free encyclopedia
Not to be confused with Transformation (genetics), the incorporation of foreign DNA by bacteria.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

Causes

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There are many causes of primary malignant transformation, or tumorigenesis. Most human cancers in the United States are caused by external factors, and these factors are largely avoidable.[1][2][3] These factors were summarized by Doll and Peto in 1981,[1] and were still considered to be valid in 2015.[2] These factors are listed in the table.

External factors in cancer
Factor Estimated percent of cancer deaths
Diet 35
Tobacco 30
Infection 10
Reproductive and sexual behaviora 7
Occupation 4
Alcohol 3
Sunlight (UV) 3
Pollution 2
Medicines and medical procedures 1
Food additives <1
Industrial products <1

a Reproductive and sexual behaviors include: number of partners; age at first menstruation; zero versus one or more live births

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Diet and colon cancer

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Colon cancer provides one example of the mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African Americans in the United States is associated with a yearly colon cancer rate of 65 per 100,000 individuals, while the high fiber/low fat diet of rural Native Africans in South Africa is associated with a yearly colon cancer rate of <5 per 100,000.[4] Feeding the Western diet for two weeks to Native Africans increased their secondary bile acids, including carcinogenic deoxycholic acid,[5] by 400%, and also changed the colonic microbiota.[4] Evidence reviewed by Sun and Kato[6] indicates that differences in human colonic microbiota play an important role in the progression of colon cancer.

Diet and lung cancer

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A second example, relating a dietary component to a cancer, is illustrated by lung cancer. Two large population-based studies were performed, one in Italy and one in the United States.[7] In Italy, the study population consisted of two cohorts: the first, 1721 individuals diagnosed with lung cancer and no severe disease, and the second, 1918 control individuals with absence of lung cancer history or any advanced diseases. All individuals filled out a food frequency questionnaire including consumption of walnuts, hazelnuts, almonds, and peanuts, and indicating smoking status. In the United States, 495,785 members of AARP were questioned on consumption of peanuts, walnuts, seeds, or other nuts in addition to other foods and smoking status. In this U.S. study 18,533 incident lung cancer cases were identified during up to 16 years of follow-up. Overall, individuals in the highest quintile of frequency of nut consumption had a 26% lower risk of lung cancer in the Italian study and a 14% lower risk of lung cancer in the U.S. study. Similar results were obtained among individuals who were smokers.

Due to tobacco

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The most important chemical compounds in smoked tobacco that are carcinogenic are those that produce DNA damage since such damage appears to be the primary underlying cause of cancer.[8] Cunningham et al.[9] combined the microgram weight of the compound in the smoke of one cigarette with the known genotoxic effect per microgram to identify the most carcinogenic compounds in cigarette smoke. These compounds and their genotoxic effects are listed in the article Cigarette. The top three compounds are acrolein, formaldehyde and acrylonitrile, all known carcinogens.

Due to infection

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Viruses

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In 2002 the World Health Organizations International Agency for Research on Cancer[10] estimated that 11.9% of human cancers are caused by one of seven viruses (see Oncovirus overview table). These are Epstein-Barr virus (EBV or HHV4); Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8); Hepatitis B and Hepatitis C viruses (HBV and HCV); Human T-lymphotrophic virus 1 (HTLV-1); Merkel cell polyomavirus (MCPyV); and a group of alpha Human papillomaviruses (HPVs).[11]

Bacteria

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Helicobacter pylori and gastric cancer

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In 1995 epidemiologic evidence indicated that Helicobacter pylori infection increases the risk for gastric carcinoma.[12] More recently, experimental evidence showed that infection with Helicobacter pylori cagA-positive bacterial strains results in severe degrees of inflammation and oxidative DNA damage, leading to progression to gastric cancer.[13]

Other bacterial roles in carcinogenesis

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Perera et al.[14] referred to a number of articles pointing to roles of bacteria in other cancers. They pointed to single studies on the role of Chlamydia trachomatis in cervical cancer, Salmonella typhi in gallbladder cancer, and both Bacteroides fragilis and Fusobacterium nucleatum in colon cancer. Meurman has recently summarized evidence connecting oral microbiota with carcinogenesis.[15] Although suggestive, these studies need further confirmation.

Common underlying factors in cancer

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Mutations

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One underlying commonality in cancers is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's somatic DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the exome). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage.[16]

Cancers also generally have genome instability, that includes a high frequency of mutations in the noncoding DNA that makes up about 98% of the human genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000.[17] In an average melanoma (where melanomas have a higher exome mutation frequency[16]) the total number of DNA sequence mutations is about 80,000.[18]

Epigenetic alterations

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Transcription silencing

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A second underlying commonality in cancers is altered epigenetic regulation of transcription. In cancers, loss of gene expression occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al.[16] point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker, or passenger, mutations.[16] In contrast, the frequency of epigenetic alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while the corresponding CpG islands are not methylated in the adjacent mucosa.[19][20][21] Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region.[22][23] In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off.[21]

Post-transcriptional silencing

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Epigenetic alterations are also carried out by another major regulatory element, that of microRNAs (miRNAs). In mammals, these small non-coding RNA molecules regulate about 60% of the transcriptional activity of protein-encoding genes.[24] Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes.[25] Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer. BRCA1 is normally expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired.[26] BRCA1 is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks.[27] BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.[28] Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.[29] BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.[30] However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.[31] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.[32] Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.[33] Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

Post-transcriptional regulation by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the three prime untranslated region of the target gene's mRNA.[34] The mechanism of translational silencing or degradation of target mRNA is implemented through the RNA-induced silencing complex (RISC).

DNA repair gene silencing

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Main articles: DNA methylation in cancer and Regulation of transcription in cancer

Silencing of a DNA repair gene by hypermethylation or other epigenetic alteration appears to be a frequent step in progression to cancer. As summarized in a review,[citation needed] promoter hypermethylation of DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. In addition, promoter hypermethylation of DNA repair genes LIG4, NEIL1, ATM, MLH1 or FANCB occurs at frequencies of between 33% and 82% in one or more of head and neck cancers, non-small-cell lung cancers or non-small-cell lung cancer squamous cell carcinomas. Further, the article Werner syndrome ATP-dependent helicase indicates the DNA repair gene WRN has a promoter that is often hypermethylated in a variety of cancers, with WRN hypermethylation occurring in 11% to 38% of colorectal, head and neck, stomach, prostate, breast, thyroid, non-Hodgkin lymphoma, chondrosarcoma and osteosarcoma cancers.

Such silencing likely acts similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer.[35] Another review[36] points out that when a gene necessary for DNA repair is epigenetically silenced, DNA repair would tend to be deficient and DNA damages can accumulate. Increased DNA damage can cause increased errors during DNA synthesis, leading to mutations that give rise to cancer.

Induced by heavy metals

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The heavy metals cadmium, arsenic and nickel are all carcinogenic when present above certain levels.[37][38][39][40]

Cadmium is known to be carcinogenic, possibly due to reduction of DNA repair. Lei et al.[41] evaluated five DNA repair genes in rats after exposure of the rats to low levels of cadmium. They found that cadmium caused repression of three of the DNA repair genes: XRCC1 needed for base excision repair, OGG1 needed for base excision repair, and ERCC1 needed for nucleotide excision repair. Repression of these genes was not due to methylation of their promoters.

Arsenic carcinogenicity was reviewed by Bhattacharjee et al.[39] They summarized the role of arsenic and its metabolites in generating oxidative stress, resulting in DNA damage. In addition to causing DNA damage, arsenic also causes repression of several DNA repair enzymes in both the base excision repair pathway and the nucleotide excision repair pathway. Bhattacharjee et al. further reviewed the role of arsenic in causing telomere dysfunction, mitotic arrest, defective apoptosis, as well as altered promoter methylation and miRNA expression. Each of these alterations could contribute to arsenic-induced carcinogenesis.

Nickel compounds are carcinogenic and occupational exposure to nickel is associated with an increased risk of lung and nasal cancers.[42] Nickel compounds exhibit weak mutagenic activity, but they considerably alter the transcriptional landscape of the DNA of exposed individuals.[42] Arita et al.[42] examined the peripheral blood mononuclear cells of eight nickel-refinery workers and ten non-exposed workers. They found 2756 differentially expressed genes with 770 up-regulated genes and 1986 down-regulated genes. DNA repair genes were significantly over-represented among the differentially expressed genes, with 29 DNA repair genes repressed in the nickel-refinery workers and two over-expressed. The alterations in gene expression appear to be due to epigenetic alterations of histones, methylations of gene promoters, and hypermethylation of at least microRNA miR-152.[40][43]

Clinical signs

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Malignant transformation of cells in a benign tumor may be detected by pathologic examination of tissues. Often the clinical signs and symptoms are suggestive of a malignant tumor. The physician, during the medical history examination, can find that there have been changes in size or patient sensation and, upon direct examination, that there has been a change in the lesion itself.

Risk assessments can be done and are known for certain types of benign tumor which are known to undergo malignant transformation. One of the better-known examples of this phenomenon is the progression of a nevus to melanoma.

See also

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References

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  1. ^ a b Doll R, Peto R (1981). "The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today". J. Natl. Cancer Inst. 66 (6): 1191–308. doi:10.1093/jnci/66.6.1192. PMID 7017215.
  2. ^ a b Blot WJ, Tarone RE (2015). "Doll and Peto's quantitative estimates of cancer risks: holding generally true for 35 years". J. Natl. Cancer Inst. 107 (4): djv044. doi:10.1093/jnci/djv044. PMID 25739419.
  3. ^ Song M, Giovannucci EL (2015). "RE: Doll and Peto's Quantitative Estimates of Cancer Risks: Holding Generally True for 35 Years". J. Natl. Cancer Inst. 107 (10): djv240. doi:10.1093/jnci/djv240. PMID 26271254.
  4. ^ a b O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM, Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S, Puylaert PG, DeLany J, Krasinskas A, Benefiel AC, Kaseb HO, Newton K, Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG (2015). "Fat, fibre and cancer risk in African Americans and rural Africans". Nat Commun. 6: 6342. Bibcode:2015NatCo...6.6342O. doi:10.1038/ncomms7342. PMC 4415091. PMID 25919227.
  5. ^ Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Arch. Toxicol. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC 3149672. PMID 21267546.
  6. ^ Sun J, Kato I (2016). "Gut microbiota, inflammation and colorectal cancer". Genes & Diseases. 3 (2): 130–143. doi:10.1016/j.gendis.2016.03.004. PMC 5221561. PMID 28078319.
  7. ^ Lee JT, Lai GY, Liao LM, Subar AF, Bertazzi PA, Pesatori AC, Freedman ND, Landi MT, Lam TK (2017). "Nut consumption and lung cancer risk: Results from two large observational studies". Cancer Epidemiol. Biomarkers Prev. 26 (6): 826–836. doi:10.1158/1055-9965.EPI-16-0806. PMC 6020049. PMID 28077426.
  8. ^ Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
  9. ^ Cunningham FH, Fiebelkorn S, Johnson M, Meredith C (2011). "A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants". Food Chem. Toxicol. 49 (11): 2921–33. doi:10.1016/j.fct.2011.07.019. PMID 21802474.
  10. ^ Parkin, Donald Maxwell (2006). "The global health burden of infection-associated cancers in the year 2002". International Journal of Cancer. 118 (12): 3030–44. doi:10.1002/ijc.21731. PMID 16404738.
  11. ^ McBride AA (2017). "Perspective: The Promise of Proteomics in the Study of Oncogenic Viruses". Mol. Cell. Proteomics. 16 (4 suppl 1): S65–S74. doi:10.1074/mcp.O116.065201. PMC 5393395. PMID 28104704.
  12. ^ Correa P (1995). "Helicobacter pylori and gastric carcinogenesis". Am. J. Surg. Pathol. 19 (Suppl 1): S37–43. PMID 7762738.
  13. ^ Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, Khan S, Kazi JI, Bernstein C, Kazmi SU (2014). "Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis". Pathol. Oncol. Res. 20 (4): 839–46. doi:10.1007/s12253-014-9762-1. PMID 24664859. S2CID 18727504.
  14. ^ Perera M, Al-Hebshi NN, Speicher DJ, Perera I, Johnson NW (2016). "Emerging role of bacteria in oral carcinogenesis: a review with special reference to perio-pathogenic bacteria". J Oral Microbiol. 8: 32762. doi:10.3402/jom.v8.32762. PMC 5039235. PMID 27677454.
  15. ^ Meurman JH (2010). "Oral microbiota and cancer". J Oral Microbiol. 2: 5195. doi:10.3402/jom.v2i0.5195. PMC 3084564. PMID 21523227.
  16. ^ a b c d Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013). "Cancer genome landscapes". Science. 339 (6127): 1546–58. Bibcode:2013Sci...339.1546V. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594.
  17. ^ Yost SE; Smith EN; Schwab RB; Bao L; Jung H; Wang X; Voest E; Pierce JP; Messer K; Parker BA; Harismendy O; Frazer KA (August 2012). "Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens". Nucleic Acids Res. 40 (14): e107. doi:10.1093/nar/gks299. PMC 3413110. PMID 22492626.
  18. ^ Berger MF; Hodis E; Heffernan TP; Deribe YL; Lawrence MS; Protopopov A; Ivanova E; Watson IR; Nickerson E; Ghosh P; Zhang H; Zeid R; Ren X; Cibulskis K; Sivachenko AY; Wagle N; Sucker A; Sougnez C; Onofrio R; Ambrogio L; Auclair D; Fennell T; Carter SL; Drier Y; Stojanov P; Singer MA; Voet D; Jing R; Saksena G; Barretina J; Ramos AH; Pugh TJ; Stransky N; Parkin M; Winckler W; Mahan S; Ardlie K; Baldwin J; Wargo J; Schadendorf D; Meyerson M; Gabriel SB; Golub TR; Wagner SN; Lander ES; Getz G; Chin L; Garraway LA (May 2012). "Melanoma genome sequencing reveals frequent PREX2 mutations". Nature. 485 (7399): 502–6. Bibcode:2012Natur.485..502B. doi:10.1038/nature11071. PMC 3367798. PMID 22622578.
  19. ^ Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP (2010). "Orphan CpG islands identify numerous conserved promoters in the mammalian genome". PLOS Genet. 6 (9): e1001134. doi:10.1371/journal.pgen.1001134. PMC 2944787. PMID 20885785.
  20. ^ Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M (2016). "Discovery and Validation of Hypermethylated Markers for Colorectal Cancer". Dis. Markers. 2016: 1–7. doi:10.1155/2016/2192853. PMC 4963574. PMID 27493446.
  21. ^ a b Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP (2013). "Whole-genome methylation analysis of benign and malignant colorectal tumours". J. Pathol. 229 (5): 697–704. doi:10.1002/path.4132. PMC 3619233. PMID 23096130.
  22. ^ Illingworth, Robert S.; Gruenewald-Schneider, Ulrike; Webb, Shaun; Kerr, Alastair R. W.; James, Keith D.; Turner, Daniel J.; Smith, Colin; Harrison, David J.; Andrews, Robert (2010-09-23). "Orphan CpG Islands Identify Numerous Conserved Promoters in the Mammalian Genome". PLOS Genetics. 6 (9): e1001134. doi:10.1371/journal.pgen.1001134. ISSN 1553-7404. PMC 2944787. PMID 20885785.
  23. ^ Saxonov, Serge; Berg, Paul; Brutlag, Douglas L. (2006-01-31). "A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters". Proceedings of the National Academy of Sciences. 103 (5): 1412–1417. Bibcode:2006PNAS..103.1412S. doi:10.1073/pnas.0510310103. ISSN 0027-8424. PMC 1345710. PMID 16432200.
  24. ^ Friedman, RC; Farh, KK; Burge, CB; Bartel, DP (January 2009). "Most mammalian mRNAs are conserved targets of microRNAs". Genome Res. 19 (1): 92–105. doi:10.1101/gr.082701.108. PMC 2612969. PMID 18955434.
  25. ^ Vrba, L; Muñoz-Rodríguez, JL; Stampfer, MR; Futscher, BW (2013). "miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer". PLOS ONE. 8 (1): e54398. Bibcode:2013PLoSO...854398V. doi:10.1371/journal.pone.0054398. PMC 3547033. PMID 23342147.
  26. ^ Bernstein C, Bernstein H, Payne CM, Garewal H (2002). "DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis". Mutat. Res. 511 (2): 145–78. Bibcode:2002MRRMR.511..145B. doi:10.1016/s1383-5742(02)00009-1. PMID 12052432.
  27. ^ Friedenson B (2007). "The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers". BMC Cancer. 7: 152. doi:10.1186/1471-2407-7-152. PMC 1959234. PMID 17683622.
  28. ^ Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ (1999). "Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas". Nat. Genet. 21 (2): 236–40. doi:10.1038/6029. PMID 9988281. S2CID 7988460.
  29. ^ Brody LC, Biesecker BB (1998). "Breast cancer susceptibility genes. BRCA1 and BRCA2". Medicine (Baltimore). 77 (3): 208–26. doi:10.1097/00005792-199805000-00006. PMID 9653432.
  30. ^ Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000). "Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors". J. Natl. Cancer Inst. 92 (7): 564–9. doi:10.1093/jnci/92.7.564. PMID 10749912.
  31. ^ Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM (2013). "MicroRNA-182-5p targets a network of genes involved in DNA repair". RNA. 19 (2): 230–42. doi:10.1261/rna.034926.112. PMC 3543090. PMID 23249749.
  32. ^ Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D (2011). "miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors". Mol. Cell. 41 (2): 210–20. doi:10.1016/j.molcel.2010.12.005. PMC 3249932. PMID 21195000.
  33. ^ Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S (2011). "Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers". EMBO Mol Med. 3 (5): 279–90. doi:10.1002/emmm.201100136. PMC 3377076. PMID 21472990.
  34. ^ Hu W, Coller J (2012). "What comes first: translational repression or mRNA degradation? The deepening mystery of microRNA function". Cell Res. 22 (9): 1322–4. doi:10.1038/cr.2012.80. PMC 3434348. PMID 22613951.
  35. ^ Jin B, Robertson KD (2013). "DNA Methyltransferases, DNA Damage Repair, and Cancer". Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology. Vol. 754. pp. 3–29. doi:10.1007/978-1-4419-9967-2_1. ISBN 978-1-4419-9966-5. PMC 3707278. PMID 22956494.
  36. ^ Bernstein C, Nfonsam V, Prasad AR, Bernstein H (2013). "Epigenetic field defects in progression to cancer". World J Gastrointest Oncol. 5 (3): 43–9. doi:10.4251/wjgo.v5.i3.43. PMC 3648662. PMID 23671730.
  37. ^ Nawrot TS, Martens DS, Hara A, Plusquin M, Vangronsveld J, Roels HA, Staessen JA (2015). "Association of total cancer and lung cancer with environmental exposure to cadmium: the meta-analytical evidence". Cancer Causes Control. 26 (9): 1281–8. doi:10.1007/s10552-015-0621-5. PMID 26109463. S2CID 9729454.
  38. ^ Cohen SM, Arnold LL, Beck BD, Lewis AS, Eldan M (2013). "Evaluation of the carcinogenicity of inorganic arsenic". Crit. Rev. Toxicol. 43 (9): 711–52. doi:10.3109/10408444.2013.827152. PMID 24040994. S2CID 26873122.
  39. ^ a b Bhattacharjee P, Banerjee M, Giri AK (2013). "Role of genomic instability in arsenic-induced carcinogenicity. A review". Environ Int. 53: 29–40. Bibcode:2013EnInt..53...29B. doi:10.1016/j.envint.2012.12.004. PMID 23314041.[permanent dead link‍]
  40. ^ a b Ji W, Yang L, Yuan J, Yang L, Zhang M, Qi D, Duan X, Xuan A, Zhang W, Lu J, Zhuang Z, Zeng G (2013). "MicroRNA-152 targets DNA methyltransferase 1 in NiS-transformed cells via a feedback mechanism". Carcinogenesis. 34 (2): 446–53. doi:10.1093/carcin/bgs343. PMID 23125218.
  41. ^ Lei YX, Lu Q, Shao C, He CC, Lei ZN, Lian YY (2015). "Expression profiles of DNA repair-related genes in rat target organs under subchronic cadmium exposure". Genet. Mol. Res. 14 (1): 515–24. doi:10.4238/2015.January.26.5. PMID 25729986.
  42. ^ a b c Arita A, Muñoz A, Chervona Y, Niu J, Qu Q, Zhao N, Ruan Y, Kiok K, Kluz T, Sun H, Clancy HA, Shamy M, Costa M (2013). "Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects". Cancer Epidemiol. Biomarkers Prev. 22 (2): 261–9. doi:10.1158/1055-9965.EPI-12-1011. PMC 3565097. PMID 23195993.
  43. ^ Sun H, Shamy M, Costa M (2013). "Nickel and epigenetic gene silencing". Genes. 4 (4): 583–95. doi:10.3390/genes4040583. PMC 3927569. PMID 24705264.
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