Genetic Epidemiology of Mismatch Repair Deficiency in Ovarian Cancer

  • Tuya PalEmail author
  • Jenny Permuth Wey
  • Thomas A. Sellers


This chapter reviews the molecular and histopathologic characteristics of ovarian cancers due to genetic defects in the MMR pathway, highlighting the clinical significance of these findings, including implications for diagnosis, prognosis and treatment as well as interactions between DNA mismatch repair (MMR) pathway and environmental risk factors for ovarian cancer. At least ten per cent of cases of ovarian cancer are due to mutations in BRCA1 and BRCA2 and an additional percentage are due to mutations in other genes, including the mismatch repair genes, MSH2, MLH1 and MSH6. Since the mismatch repair pathway may be impaired in up to one-fifth of ovarian tumors, categorization of ovarian cancers into subtypes based on mismatch repair deficiency is likely to permit more accurate assessment of potential etiologic associations. Furthermore, specific chemotherapeutic regimens may exist specifically for ovarian cancers with microsatellite instability, to improve treatment efficacy and reduce toxicity of drugs which may provide no added benefit. Hence clarification of epigenetic—environment interactions in a large-scale study of ovarian cancers may stimulate the development of novel chemotherapy agents.


Environmental risk factors Genetic defects in DNA mismatch repair (MMR) pathway Ovarian cancers 


  1. Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. Dec 20 1995;64(6):430–433.PubMedCrossRefGoogle Scholar
  2. Aarnio M, Sankila R, Pukkala E et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. Apr 12 1999;81(2):214–218.PubMedCrossRefGoogle Scholar
  3. Aebi S, Kurdi-Haidar B, Gordon R et al. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. Jul 1 1996;56(13):3087–3090.PubMedGoogle Scholar
  4. Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI. Growth patterns and the risk of breast cancer in women. N Engl J Med. Oct 14 2004;351(16):1619–1626.PubMedCrossRefGoogle Scholar
  5. Akiyama Y, Nagasaki H, Nakajima T, Sakai H, Nomizu T, Yuasa Y. Infrequent frameshift mutations in the simple repeat sequences of hMLH3 in hereditary nonpolyposis colorectal cancers. Jpn J Clin Oncol. Feb 2001;31(2):61–64.PubMedCrossRefGoogle Scholar
  6. Akiyama Y, Sato H, Yamada T et al. Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res. Sep 15 1997a;57(18):3920–3923.PubMedGoogle Scholar
  7. Akiyama Y, Tsubouchi N, Yuasa Y. Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers. Biochem Biophys Res Commun. Jul 18 1997b;236(2):248–252.PubMedCrossRefGoogle Scholar
  8. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. Feb 2001;158(2):527–535.PubMedCrossRefGoogle Scholar
  9. American Cancer Society I. Cancer Facts & Figures 2004. [Internet] Accessed 2004, 2004.
  10. American Cancer Society I. Cancer Facts & Figures 2007. [Internet] Accessed 2007, 2007.
  11. Anthoney DA, McIlwrath AJ, Gallagher WM, Edlin AR, Brown R. Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells. Cancer Res. Mar 15 1996;56(6):1374–1381.PubMedGoogle Scholar
  12. Arnold CN, Goel A, Boland CR. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int J Cancer. Aug 10 2003;106(1):66–73.PubMedCrossRefGoogle Scholar
  13. Arzimanoglou II, Lallas T, Osborne M, Barber H, Gilbert F. Microsatellite instability differences between familial and sporadic ovarian cancers. Carcinogenesis. Sep 1996;17(9):1799–1804.PubMedCrossRefGoogle Scholar
  14. Baker JA, Boakye K, McCann SE et al. Consumption of black tea or coffee and risk of ovarian cancer. Int J Gynecol Cancer. Jan-Feb 2007;17(1):50–54.PubMedCrossRefGoogle Scholar
  15. Beral V, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. May 19 2007;369(9574):1703–1710.PubMedCrossRefGoogle Scholar
  16. Berends MJ, Wu Y, Sijmons RH et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. Jan 2002;70(1):26–37.PubMedCrossRefGoogle Scholar
  17. Bettstetter M, Dechant S, Ruemmele P et al. Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res. Jun 1 2007;13(11):3221–3228.PubMedCrossRefGoogle Scholar
  18. Bewtra C, Watson P, Conway T, Read-Hippee C, Lynch HT. Hereditary ovarian cancer: a clinicopathological study. Int J Gynecol Pathol. 1992;11:180–187.PubMedCrossRefGoogle Scholar
  19. Boland CR, Thibodeau SN, Hamilton SR et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. Nov 15 1998;58(22):5248–5257.PubMedGoogle Scholar
  20. Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer. Oct 1989;60(4):592–598.PubMedCrossRefGoogle Scholar
  21. Bray F, Loos AH, Tognazzo S, La Vecchia C. Ovarian cancer in Europe: Cross-sectional trends in incidence and mortality in 28 countries, 1953–2000. Int J Cancer. Mar 1 2005;113(6):977–990.PubMedCrossRefGoogle Scholar
  22. Breivik J, Lothe RA, Meling GI, Rognum TO, Borresen-Dale AL, Gaudernack G. Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors. Int J Cancer. Dec 19 1997;74(6):664–669.PubMedCrossRefGoogle Scholar
  23. Brinton LA, Sakoda LC, Sherman ME et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev. Dec 2005;14(12):2929–2935.PubMedCrossRefGoogle Scholar
  24. Bronner CE, Baker SM, Morrison PT et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. Mar 17 1994;368(6468):258–261.PubMedCrossRefGoogle Scholar
  25. Brown R, Hirst GL, Gallagher WM et al. hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene. Jul 3 1997;15(1):45–52.PubMedCrossRefGoogle Scholar
  26. Brown GJ, St John DJ, Macrae FA, Aittomaki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol. Mar 2001;80(3):346–349.PubMedCrossRefGoogle Scholar
  27. Bubb VJ, Curtis LJ, Cunningham C et al. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. Jun 20 1996;12(12):2641–2649.PubMedGoogle Scholar
  28. Buller RE, Shahin MS, Holmes RW, Hatterman M, Kirby PA, Sood AK. p53 Mutations and microsatellite instability in ovarian cancer: Yin and yang. Am J Obstet Gynecol. Apr 2001;184(5):891–902; discussion 902–893.PubMedCrossRefGoogle Scholar
  29. Cai KQ, Albarracin C, Rosen D et al. Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma. Hum Pathol. May 2004;35(5):552–559.PubMedCrossRefGoogle Scholar
  30. Casagrande JT, Louie EW, Pike MC, Roy S, Ross RK, Henderson BE. “Incessant ovulation” and ovarian cancer. Lancet. Jul 28 1979;2(8135):170–173.PubMedCrossRefGoogle Scholar
  31. Cawkwell L, Gray S, Murgatroyd H et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut. Sep 1999;45(3):409–415.PubMedCrossRefGoogle Scholar
  32. Cederquist K, Emanuelsson M, Wiklund F, Golovleva I, Palmqvist R, Gronberg H. Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome. Clin Genet. Dec 2005;68(6):533–541.PubMedCrossRefGoogle Scholar
  33. Chao A, Gilliland F, Willman C et al. Patient and tumor characteristics of colon cancers with microsatellite instability: a population-based study. Cancer Epidemiol Biomarkers Prev. Jun 2000;9(6):539–544.PubMedGoogle Scholar
  34. Chiaravalli AM, Furlan D, Facco C et al. Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences. Virchows Arch. Jan 2001;438(1):39–48.PubMedCrossRefGoogle Scholar
  35. Clendenning M, Hampel H, LaJeunesse J et al. Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat. May 2006;27(5):490–495.PubMedCrossRefGoogle Scholar
  36. Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst. Oct 1983;71(4):717–721.PubMedGoogle Scholar
  37. Crijnen TE, Janssen-Heijnen ML, Gelderblom H et al. Survival of patients with ovarian cancer due to a mismatch repair defect. Fam Cancer. 2005;4(4):301–305.PubMedCrossRefGoogle Scholar
  38. Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. A prospective study of postmenopausal hormone use and ovarian cancer risk. Br J Cancer. Jan 15 2007;96(1):151–156.PubMedCrossRefGoogle Scholar
  39. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature. Jun 27 2002;417(6892):949–954.PubMedCrossRefGoogle Scholar
  40. de Jong AE, van Puijenbroek M, Hendriks Y et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res. Feb 1 2004;10(3):972–980.PubMedCrossRefGoogle Scholar
  41. de la Chapelle A. Microsatellite instability. N Engl J Med. Jul 17 2003;349(3):209–210.PubMedCrossRefGoogle Scholar
  42. de la Chapelle A. The incidence of Lynch syndrome. Fam Cancer. 2005;4(3):233–237.PubMedCrossRefGoogle Scholar
  43. de Leeuw WJ, Dierssen J, Vasen HF et al. Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol. Nov 2000;192(3):328–335.PubMedCrossRefGoogle Scholar
  44. Dellas A, Puhl A, Schraml P et al. Molecular and clinicopathological analysis of ovarian carcinomas with and without microsatellite instability. Anticancer Res. Jan-Feb 2004;24(1):361–369.PubMedGoogle Scholar
  45. Deng G, Bell I, Crawley S et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. Jan 1 2004;10(1 Pt 1):191–195.PubMedCrossRefGoogle Scholar
  46. Deng G, Chen A, Hong J, Chae HS, Kim YS. Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. May 1 1999;59(9):2029–2033.PubMedGoogle Scholar
  47. Deng D, Deng G, Smith MF et al. Simultaneous detection of CpG methylation and single nucleotide polymorphism by denaturing high performance liquid chromatography. Nucleic Acids Res. Feb 1 2002;30(3):E13.PubMedCrossRefGoogle Scholar
  48. Diergaarde B, Vrieling A, van Kraats AA, van Muijen GN, Kok FJ, Kampman E. Cigarette smoking and genetic alterations in sporadic colon carcinomas. Carcinogenesis. Mar 2003;24(3):565–571.PubMedCrossRefGoogle Scholar
  49. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. Nov 1 1997;57(21):4749–4756.PubMedGoogle Scholar
  50. Dolcetti R, Viel A, Doglioni C et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. Jun 1999;154(6):1805–1813.PubMedCrossRefGoogle Scholar
  51. Domanska K, Malander S, Masback A, Nilbert M. Ovarian cancer at young age: the contribution of mismatch-repair defects in a population-based series of epithelial ovarian cancer before age 40. Int J Gynecol Cancer. Jul-Aug 2007;17(4):789–793.PubMedCrossRefGoogle Scholar
  52. Domingo E, Espin E, Armengol M et al. Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer. Feb 2004;39(2):138–142.PubMedCrossRefGoogle Scholar
  53. Douglas JA, Gruber SB, Meister KA et al. History and molecular genetics of Lynch syndrome in family G: a century later. J Am Med Assoc. Nov 2 2005;294(17):2195–2202.CrossRefGoogle Scholar
  54. Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. May 20 2000;355(9217):1745–1750.PubMedCrossRefGoogle Scholar
  55. Elsaleh H, Powell B, McCaul K et al. P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res. May 2001;7(5):1343–1349.PubMedGoogle Scholar
  56. Esteller M, Catasus L, Matias-Guiu X et al. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol. Nov 1999;155(5):1767–1772.PubMedCrossRefGoogle Scholar
  57. Fang DC, Wang RQ, Yang SM et al. Mutation and methylation of hMLH1 in gastric carcinomas with microsatellite instability. World J Gastroenterol. Apr 2003;9(4):655–659.PubMedGoogle Scholar
  58. Farrow DC, Weiss NS, Lyon JL, Daling JR. Association of obesity and ovarian cancer in a case-control study. Am J Epidemiol. Jun 1989;129(6):1300–1304.PubMedGoogle Scholar
  59. Fathalla MF. Incessant ovulation–a factor in ovarian neoplasia? Lancet. Jul 17 1971;2(7716):163.PubMedCrossRefGoogle Scholar
  60. Fishel R, Lescoe MK, Rao MR et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. Dec 3 1993;75(5):1027–1038.PubMedCrossRefGoogle Scholar
  61. Fleisher AS, Esteller M, Tamura G et al. Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene. Jan 18 2001;20(3):329–335.PubMedCrossRefGoogle Scholar
  62. Forster S, Sattler HP, Hack M et al. Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery. Jan 1998;123(1):13–18.PubMedCrossRefGoogle Scholar
  63. Franceschi S, La Vecchia C, Booth M et al. Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause. Int J Cancer. Aug 19 1991;49(1):57–60.PubMedCrossRefGoogle Scholar
  64. Froggatt NJ, Green J, Brassett C et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J Med Genet. Feb 1999;36(2):97–102.PubMedGoogle Scholar
  65. Fujita M, Enomoto T, Yoshino K et al. Microsatellite instability and alterations in the hMSH2 gene in human ovarian cancer. Int J Cancer. 1995;64:361–366.PubMedCrossRefGoogle Scholar
  66. Geisler JP, Goodheart MJ, Sood AK, Holmes RJ, Hatterman-Zogg MA, Buller RE. Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma. Cancer. Nov 15 2003;98(10):2199–2206.PubMedCrossRefGoogle Scholar
  67. Gemignani ML, Schlaerth AC, Bogomolniy F et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol. Aug 2003;90(2):378–381.PubMedCrossRefGoogle Scholar
  68. Giacchero A, Aste H, Baracchini P et al. Primary signet-ring carcinoma of the large bowel. Report of nine cases. Cancer. Dec 1 1985;56(11):2723–2726.PubMedCrossRefGoogle Scholar
  69. Giovannucci E. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. Jul 2001;10(7):725–731.PubMedGoogle Scholar
  70. Gras E, Catasus L, Arguelles R et al. Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer. Dec 1 2001;92(11):2829–2836.PubMedCrossRefGoogle Scholar
  71. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. Jan–Feb 2001;51(1):15–36.PubMedCrossRefGoogle Scholar
  72. Gryfe R, Kim H, Hsieh ET et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69–77.PubMedCrossRefGoogle Scholar
  73. Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL. Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol. 1990;43(6):559–568.PubMedCrossRefGoogle Scholar
  74. Haas CJ, Diebold J, Hirschmann A, Rohrbach H, Schmid S, Lohrs U. Microsatellite analysis in serous tumors of the ovary. Int J Gynecol Pathol. Apr 1999;18(2):158–162.PubMedCrossRefGoogle Scholar
  75. Halling KC, French AJ, McDonnell SK et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. Aug 4 1999;91(15):1295–1303.PubMedCrossRefGoogle Scholar
  76. Halvarsson B, Lindblom A, Rambech E, Lagerstedt K, Nilbert M. The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer. Fam Cancer. 2006;5(4):353–358.PubMedCrossRefGoogle Scholar
  77. Hamilton SR, Liu B, Parsons RE et al. The molecular basis of Turcot’s syndrome. N Engl J Med. Mar 30 1995;332(13):839–847.PubMedCrossRefGoogle Scholar
  78. Han HJ, Yanagisawa A, Kato Y, Park JG, Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res. Nov 1 1993;53(21):5087–5089.PubMedGoogle Scholar
  79. Hankinson SE, Colditz GA, Hunter DJ et al. A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer. Jul 15 1995;76(2):284–290.PubMedCrossRefGoogle Scholar
  80. Helleman J, van Staveren IL, Dinjens WN et al. Mismatch repair and treatment resistance in ovarian cancer. BMC Cancer. 2006;6:201.PubMedCrossRefGoogle Scholar
  81. Hemminki K, Granstrom C. Familial clustering of ovarian and endometrial cancers. Eur J Cancer. Jan 2004;40(1):90–95.PubMedCrossRefGoogle Scholar
  82. Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. Oct 2000;119(4):921–928.PubMedCrossRefGoogle Scholar
  83. Hemminki A, Peltomaki P, Mecklin JP et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. Dec 1994;8(4):405–410.PubMedCrossRefGoogle Scholar
  84. Hendriks YM, Jagmohan-Changur S, van der Klift HM et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. Feb 2006;130(2):312–322.PubMedCrossRefGoogle Scholar
  85. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. Sep 3 1996;93(18):9821–9826.PubMedCrossRefGoogle Scholar
  86. Hickey KP, Boyle KP, Jepps HM, Andrew AC, Buxton EJ, Burns PA. Molecular detection of tumour DNA in serum and peritoneal fluid from ovarian cancer patients. Br J Cancer. Aug 1999;80(11):1803–1808.PubMedCrossRefGoogle Scholar
  87. Hienonen T, Laiho P, Salovaara R et al. Little evidence for involvement of MLH3 in colorectal cancer predisposition. Int J Cancer. Aug 20 2003;106(2):292–296.PubMedCrossRefGoogle Scholar
  88. Ho SM. Estrogen, Progesterone and Epithelial Ovarian Cancer. Reprod Biol Endocrinol. Oct 7 2003;1(1):73.PubMedCrossRefGoogle Scholar
  89. Huang J, Kuismanen SA, Liu T et al. MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer Res. Feb 15 2001;61(4):1619–1623.PubMedGoogle Scholar
  90. Ichikawa Y, Lemon SJ, Wang S et al. Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members. Cancer Genet Cytogenet. Jul 1 1999;112(1):2–8.PubMedCrossRefGoogle Scholar
  91. Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: The interrelationship between genetics and epigenetics. Carcinogenesis. 2007 Oct 17;29(4):673–680.PubMedCrossRefGoogle Scholar
  92. Ishiguro K, Kawakami K, Maeda K, Ishida Y, Omura K, Watanabe G. Microsatellite instability in gastric cancer is closely associated with hMLH1 hypermethylation at the proximal region of the promoter. Int J Mol Med. Oct 2003;12(4):603–608.PubMedGoogle Scholar
  93. Iwabuchi H, Sakamoto M, Sakunaga H et al. Genetic analysis of benign, low-grade, and high-grade ovarian tumors. Cancer Res. Dec 15 1995;55(24):6172–6180.PubMedGoogle Scholar
  94. Jager AC, Bisgaard ML, Myrhoj T, Bernstein I, Rehfeld JF, Nielsen FC. Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression. Am J Hum Genet. Jul 1997;61(1):129–138.PubMedCrossRefGoogle Scholar
  95. Jascur T, Boland CR. Structure and function of the components of the human DNA mismatch repair system. Int J Cancer. Nov 1 2006;119(9):2030–2035.PubMedCrossRefGoogle Scholar
  96. Jass JR. Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci. Jun 2000;910:62–73; discussion 73–64.PubMedCrossRefGoogle Scholar
  97. Jass JR, Biden KG, Cummings MC et al. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol. Jun 1999;52(6):455–460.PubMedCrossRefGoogle Scholar
  98. Jass JR, Do KA, Simms LA et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut. May 1998;42(5):673–679.PubMedCrossRefGoogle Scholar
  99. Jiricny J. Mismatch repair: the praying hands of fidelity. Curr Biol. Nov 2 2000;10(21):R788–R790.PubMedCrossRefGoogle Scholar
  100. Jiricny J, Nystrom-Lahti M. Mismatch repair defects in cancer. Curr Opin Genet Dev. Apr 2000;10(2):157–161.PubMedCrossRefGoogle Scholar
  101. Jo WS, Carethers JM. Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomark. 2006;2(1–2):51–60.PubMedGoogle Scholar
  102. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. Feb 1999;21(2):163–167.PubMedCrossRefGoogle Scholar
  103. Jordan SJ, Whiteman DC, Purdie DM, Green AC, Webb PM. Does smoking increase risk of ovarian cancer? A systematic review. Gynecol Oncol. Dec 2006;103(3):1122–1129.PubMedCrossRefGoogle Scholar
  104. Kampman E, Potter JD, Slattery ML, Caan BJ, Edwards S. Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control. Mar 1997;8(2):146–158.PubMedCrossRefGoogle Scholar
  105. Kane MF, Loda M, Gaida GM et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. Mar 1 1997;57(5):808–811.PubMedGoogle Scholar
  106. Kaye SB. Ovarian cancer, from the laboratory to the clinic: challenges for the future. Ann Oncol. Jan 1996;7(1):9–13.PubMedCrossRefGoogle Scholar
  107. Kim GP, Colangelo LH, Wieand HS et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. Mar 1 2007;25(7):767–772.PubMedCrossRefGoogle Scholar
  108. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. Jul 1994;145(1):148–156.PubMedGoogle Scholar
  109. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. Apr 1 2003;63(7):1454–1457.PubMedGoogle Scholar
  110. King BL, Carcangiu ML, Carter D et al. Microsatellite instability in ovarian neoplasms. Br J Cancer. 1995;72:376–382.PubMedCrossRefGoogle Scholar
  111. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. Apr 1971;68(4):820–823.PubMedCrossRefGoogle Scholar
  112. Kobayashi K, Sagae S, Kudo R, Saito H, Koi S, Nakamura Y. Microsatellite instability in endometrial carcinomas. Genes, Chromosomes and Cancer. 1995;14:128–132.CrossRefGoogle Scholar
  113. Kolodner RD, Tytell JD, Schmeits JL et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. Oct 15 1999;59(20):5068–5074.PubMedGoogle Scholar
  114. Konishi M, Kikuchi-Yanoshita R, Tanaka K et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology. Aug 1996;111(2):307–317.PubMedCrossRefGoogle Scholar
  115. Krajinovic M, Richer C, Gorska-Flipot I et al. Genomic loci susceptible to replication errors in cancer cells. Br J Cancer. Oct 1998;78(8):981–985.PubMedCrossRefGoogle Scholar
  116. Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomaki P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol. May 2000;156(5):1773–1779.PubMedCrossRefGoogle Scholar
  117. Kumar R, Angelini S, Hemminki K. Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9. Oncogene. Dec 18 2003;22(58):9217–9224.PubMedCrossRefGoogle Scholar
  118. Kvale G, Heuch I, Nilssen S, Beral V. Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer. Aug 15 1988;42(2):246–251.PubMedCrossRefGoogle Scholar
  119. Lamberti C, Lundin S, Bogdanow M et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis. Feb 2007;22(2):145–152.PubMedCrossRefGoogle Scholar
  120. Lawes DA, SenGupta S, Boulos PB. The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol. Apr 2003;29(3):201–212.PubMedCrossRefGoogle Scholar
  121. Leach FS, Nicolaides NC, Papadopoulos N et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. Dec 17 1993;75(6):1215–1225.PubMedCrossRefGoogle Scholar
  122. Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res. Jan 1 1999;59(1):159–164.PubMedGoogle Scholar
  123. Lipkin SM, Rozek LS, Rennert G et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet. Jul 2004;36(7):694–699.PubMedCrossRefGoogle Scholar
  124. Lipkin SM, Wang V, Jacoby R et al. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet. Jan 2000;24(1):27–35.PubMedCrossRefGoogle Scholar
  125. Lipkin SM, Wang V, Stoler DL et al. Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. Hum Mutat. May 2001;17(5):389–396.PubMedCrossRefGoogle Scholar
  126. Liu J, Albarracin CT, Chang KH et al. Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer. Mod Pathol. Jan 2004;17(1):75–80.PubMedCrossRefGoogle Scholar
  127. Liu B, Parsons R, Papadopoulos N et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med. Feb 1996;2(2):169–174.PubMedCrossRefGoogle Scholar
  128. Liu HX, Zhou XL, Liu T et al. The role of hMLH3 in familial colorectal cancer. Cancer Res. Apr 15 2003;63(8):1894–1899.PubMedGoogle Scholar
  129. Lothe RA, Peltomaki P, Meling GI et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993;53:5849–5852.PubMedGoogle Scholar
  130. Loukola A, Vilkki S, Singh J, Launonen V, Aaltonen LA. Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. Am J Pathol. Aug 2000;157(2):347–352.PubMedCrossRefGoogle Scholar
  131. Lubomierski N, Plotz G, Wormek M et al. BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer. Sep 1 2005;104(5):952–961.PubMedCrossRefGoogle Scholar
  132. Lukish JR, Muro K, DeNobile J et al. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg. Jan 1998;227(1):51–56.PubMedCrossRefGoogle Scholar
  133. Lynch HT, Krush AJ. Cancer family “G” revisited: 1895–1970. Cancer. Jun 1971;27(6):1505–1511.PubMedCrossRefGoogle Scholar
  134. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med. Feb 1966;117(2):206–212.PubMedCrossRefGoogle Scholar
  135. Lynch HT, Smyrk TC, Watson P et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. May 1993;104(5):1535–1549.PubMedGoogle Scholar
  136. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. Nov 1999;36(11):801–818.PubMedGoogle Scholar
  137. Malander S, Rambech E, Kristoffersson U et al. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol. May 2006;101(2):238–243.PubMedCrossRefGoogle Scholar
  138. Malander S, Ridderheim M, Masback A et al. One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer. Feb 2004;40(3):422–428.PubMedCrossRefGoogle Scholar
  139. Marcelis CL, Van Der Putten HW, Tops C, Lutgens LC, Moog U. Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? Fam Cancer. 2001;1(2):109–111.CrossRefGoogle Scholar
  140. Marcus VA, Madlensky L, Gryfe R et al. Immunohistochemistry for hMLH1 and hMSH2: A practical test for DNA mismatch repair-deficient tumors. Am J Surg Pathol. 1999;23(10):1248–1255.PubMedCrossRefGoogle Scholar
  141. Marcus PM, Newcomb PA, Young T, Storer BE. The association of reproductive and menstrual characteristics and colon and rectal cancer risk in Wisconsin women. Ann Epidemiol. Jul 1995;5(4):303–309.PubMedCrossRefGoogle Scholar
  142. Massey A, Offman J, Macpherson P, Karran P. DNA mismatch repair and acquired cisplatin resistance in E. coli and human ovarian carcinoma cells. DNA Repair (Amst). Jan 2 2003;2(1):73–89.CrossRefGoogle Scholar
  143. Mayr D, Hirschmann A, Lohrs U, Diebold J. KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol. Dec 2006;103(3):883–887.PubMedCrossRefGoogle Scholar
  144. McGivern A, Wynter CV, Whitehall VL et al. Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer. 2004;3(2):101–107.PubMedCrossRefGoogle Scholar
  145. Mecklin JP, Sipponen P, Jarvinen HJ. Histopathology of colorectal carcinomas and adenomas in cancer family syndrome. Dis Colon Rectum. Dec 1986;29(12):849–853.PubMedCrossRefGoogle Scholar
  146. Miyaki M, Konishi M, Tanaka K et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. Nov 1997;17(3):271–272.PubMedCrossRefGoogle Scholar
  147. Mok SC, Chao J, Skates S et al. Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology. J Natl Cancer Inst. Oct 3 2001;93(19):1458–1464.PubMedCrossRefGoogle Scholar
  148. Moreno-Bueno G, Gamallo C, Perez-Gallego L, de Mora JC, Suarez A, Palacios J. beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol. Jun 2001;10(2):116–122.PubMedCrossRefGoogle Scholar
  149. Myrhoj T, Bisgaard ML, Bernstein I, Svendsen LB, Sondergaard JO, Bulow S. Hereditary non-polyposis colorectal cancer: clinical features and survival. Results from the Danish HNPCC register. Scand J Gastroenterol. Jun 1997;32(6):572–576.PubMedCrossRefGoogle Scholar
  150. Narod SA, Madlensky L, Bradley L et al. Hereditary and familial ovarian cancer in Southern Ontario. Cancer. 1994a;74:2341–2346.PubMedCrossRefGoogle Scholar
  151. Narod SA, Tonin P, Lynch H, Watson P, Feunteun J, Lenoir G. Histology of BRCA-1 associated ovarian tumours. Lancet. 1994b;343:236.PubMedCrossRefGoogle Scholar
  152. Nicolaides NC, Papadopoulos N, Liu B et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. Sep 1 1994;371(6492):75–80.PubMedCrossRefGoogle Scholar
  153. Nystrom-Lahti M, Kristo P, Nicolaides NC et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med. Nov 1995;1(11):1203–1206.PubMedCrossRefGoogle Scholar
  154. Nystrom-Lahti M, Wu Y, Moisio AL et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet. Jun 1996;5(6):763–769.PubMedCrossRefGoogle Scholar
  155. Ohwada M, Suzuki M, Saga Y, Sato I. DNA replication errors are frequent in mucinous cystadenocarcinoma of the ovary. Cancer Genet Cytogenet. Feb 2000;117(1):61–65.PubMedCrossRefGoogle Scholar
  156. Ollikainen M, Hannelius U, Lindgren CM, Abdel-Rahman WM, Kere J, Peltomaki P. Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene. Jul 5 2007;26(31):4541–4549.PubMedCrossRefGoogle Scholar
  157. Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer. Mar 2007;43(4):690–709.PubMedCrossRefGoogle Scholar
  158. Orth K, Hung J, Gazdar A, Bowcock A, Mathis JM, Sambrook J. Genetic instability in human ovarian cancer cell lines. Proc Natl Acad Sci. 1994;91:9495–9499.PubMedCrossRefGoogle Scholar
  159. Papadopoulos N, Lindblom A. Molecular basis of HNPCC: mutations of MMR genes. Hum Mutat. 1997;10(2):89–99.PubMedCrossRefGoogle Scholar
  160. Papadopoulos N, Nicolaides NC, Wei YF et al. Mutation of a mutL homolog in hereditary colon cancer. Science. Mar 18 1994;263(5153):1625–1629.PubMedCrossRefGoogle Scholar
  161. Parazzini F, La Vecchia C, Negri E, Gentile A. Menstrual factors and the risk of epithelial ovarian cancer. J Clin Epidemiol. 1989;42(5):443–448.PubMedCrossRefGoogle Scholar
  162. Parsons R, Li GM, Longley MJ et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. Dec 17 1993;75(6):1227–1236.PubMedCrossRefGoogle Scholar
  163. Peltomaki P, Lothe RA, Aaltonen LA et al. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res. Dec 15 1993;53(24):5853–5855.PubMedGoogle Scholar
  164. Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology. Oct 1997;113(4):1146–1158.PubMedCrossRefGoogle Scholar
  165. Perucho M. Cancer of the microsatellite mutator phenotype. Biol Chem. Nov 1996;377(11):675–684.PubMedGoogle Scholar
  166. Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. Sep 2001;93(1–2):53–62.PubMedCrossRefGoogle Scholar
  167. Plaschke J, Kruppa C, Tischler R et al. Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer. Int J Cancer. Mar 1 2000;85(5):606–613.PubMedCrossRefGoogle Scholar
  168. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. Nov 1 2000;60(21):6039–6044.PubMedGoogle Scholar
  169. Polato F, Broggini M. Microsatellite instability and genetic alterations in ovarian cancer. Minerva Ginecol. 2003;55:129–138.PubMedGoogle Scholar
  170. Prat F, Ribe A, Gallardo A. Hereditary ovarian cancer. Hum Pathol. 2005;36:861–870.PubMedCrossRefGoogle Scholar
  171. Purdie D, Green A, Bain C et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study. Survey of Women’s Health Study Group. Int J Cancer. Sep 15 1995;62(6):678–684.PubMedCrossRefGoogle Scholar
  172. Quirk JT, Natarajan N. Ovarian cancer incidence in the United States, 1992–1999. Gynecol Oncol. May 2005;97(2):519–523.PubMedCrossRefGoogle Scholar
  173. Radman M, Wagner R. Missing mismatch repair. Nature. 1993;366:722.PubMedCrossRefGoogle Scholar
  174. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. Aug 29 2002;418(6901):934.PubMedCrossRefGoogle Scholar
  175. Rhyu MS. Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. J Natl Cancer Inst. Mar 6 1996;88(5):240–251.PubMedCrossRefGoogle Scholar
  176. Ribic CM, Sargent DJ, Moore MJ et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. Jul 17 2003;349(3):247–257.PubMedCrossRefGoogle Scholar
  177. Rigau V, Sebbagh N, Olschwang S et al. Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med. Jun 2003;127(6):694–700.PubMedGoogle Scholar
  178. Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. J Am Med Assoc. Mar 21 2001;285(11):1460–1465.CrossRefGoogle Scholar
  179. Rodriguez-Bigas MA, Boland CR, Hamilton SR et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. Dec 3 1997;89(23):1758–1762.PubMedCrossRefGoogle Scholar
  180. Rosen DG, Cai KQ, Luthra R, Liu J. Immunohistochemical staining of hMLH1 and hMSH2 reflects microsatellite instability status in ovarian carcinoma. Mod Pathol. Nov 2006;19(11):1414–1420.PubMedGoogle Scholar
  181. Rosenblatt KA, Thomas DB. Lactation and the risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol. Apr 1993;22(2):192–197.PubMedCrossRefGoogle Scholar
  182. Russell SE, McCluggage WG. A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes. J Pathol. Jun 2004;203(2):617–619.PubMedCrossRefGoogle Scholar
  183. Ruszkiewicz A, Bennett G, Moore J et al. Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours. Pathology. Dec 2002;34(6):541–547.PubMedCrossRefGoogle Scholar
  184. Samad AK, Taylor RS, Marshall T, Chapman MA. A meta-analysis of the association of physical activity with reduced risk of colorectal cancer. Colorectal Dis. May 2005;7(3):204–213.PubMedCrossRefGoogle Scholar
  185. Samimi G, Fink D, Varki NM et al. Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy. Clin Cancer Res. Apr 2000;6(4):1415–1421.PubMedGoogle Scholar
  186. Scartozzi M, De Nictolis M, Galizia E et al. Loss of hMLH1 expression correlates with improved survival in stage III-IV ovarian cancer patients. Eur J Cancer. May 2003;39(8):1144–1149.PubMedCrossRefGoogle Scholar
  187. Schafmayer C, Buch S, Egberts JH et al. Genetic investigation of DNA-repair pathway genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1 in sporadic colon cancer. Int J Cancer. Aug 1 2007;121(3):555–558.PubMedCrossRefGoogle Scholar
  188. Schink JC. Managing the care of patients with advanced ovarian cancer. Semin Oncol. 1999;26(1 Suppl 1):59–61.PubMedGoogle Scholar
  189. Schulz M, Lahmann PH, Riboli E, Boeing H. Dietary determinants of epithelial ovarian cancer: a review of the epidemiologic literature. Nutr Cancer. 2004;50(2):120–140.PubMedCrossRefGoogle Scholar
  190. Schwartz PE, Taylor KJ. Is early detection of ovarian cancer possible? Ann Med. Oct 1995;27(5):519–528.PubMedCrossRefGoogle Scholar
  191. Seidman JD, Horkayne-Szakaly I, Haiba M, Boice CR, Kurman RJ, Ronnett BM. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol. Jan 2004;23(1):41–44.PubMedCrossRefGoogle Scholar
  192. Shannon C, Kirk J, Barnetson R et al. Incidence of microsatellite instability in synchronous tumors of the ovary and endometrium. Clin Cancer Res. Apr 2003;9(4):1387–1392.PubMedGoogle Scholar
  193. Shenson DL, Gallion HH, Powell DE, Pieretti M. Loss of heterozygosity and genomic instability in synchronous endometrioid tumors of the ovary and endometrium. Cancer. Aug 15 1995;76(4):650–657.PubMedCrossRefGoogle Scholar
  194. Sieben NL, Kolkman-Uljee SM, Flanagan AM et al. Molecular genetic evidence for monoclonal origin of bilateral ovarian serous borderline tumors. Am J Pathol. Apr 2003;162(4):1095–1101.PubMedCrossRefGoogle Scholar
  195. Simpkins SB, Bocker T, Swisher EM et al. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet. Apr 1999;8(4):661–666.PubMedCrossRefGoogle Scholar
  196. Singer G, Kallinowski T, Hartmann A et al. Different types of microsatellite instability in ovarian carcinoma. Int J Cancer. Nov 20 2004;112(4):643–646.PubMedCrossRefGoogle Scholar
  197. Singer G, Oldt R 3rd, Cohen Y et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst. Mar 19 2003;95(6):484–486.PubMedCrossRefGoogle Scholar
  198. Slattery ML, Curtin K, Anderson K et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst. Nov 15 2000;92(22):1831–1836.PubMedCrossRefGoogle Scholar
  199. Slattery ML, Potter JD, Curtin K et al. Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res. Jan 1 2001;61(1):126–130.PubMedGoogle Scholar
  200. Song H, Ramus SJ, Quaye L et al. Common variants in mismatch repair genes and risk of invasive ovarian cancer. Carcinogenesis. Nov 2006;27(11):2235–2242.PubMedCrossRefGoogle Scholar
  201. Sood AK, Buller RE. Genomic instability in ovarian cancer: a reassessment using an arbitrarily primed polymerase chain reaction. Oncogene. Dec 5 1996;13(11):2499–2504.PubMedGoogle Scholar
  202. Sood AK, Holmes R, Hendrix MJ, Buller RE. Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer. Cancer Res. Jun 1 2001;61(11):4371–4374.PubMedGoogle Scholar
  203. Strathdee G, Appleton K, Illand M et al. Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes. Am J Pathol. Mar 2001;158(3):1121–1127.PubMedCrossRefGoogle Scholar
  204. Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene. Apr 8 1999;18(14):2335–2341.PubMedCrossRefGoogle Scholar
  205. Stratton JF, Thompson D, Bobrow L et al. The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study. Am J Hum Genet. Dec 1999;65(6):1725–1732.PubMedCrossRefGoogle Scholar
  206. Suchy J, Kurzawski G, Jakubowska A, Lubinski J. Ovarian cancer of endometrioid type as part of the MSH6gene mutation phenotype. J Hum Genet. 2002;47(10):529–531.PubMedCrossRefGoogle Scholar
  207. Tannergard P, Liu T, Weger A, Nordenskjold M, Lindblom A. Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer. Hum Genet. Nov 1997;101(1):51–55.PubMedCrossRefGoogle Scholar
  208. Taylor KJ, Schwartz PE. Screening for early ovarian cancer. Radiology. Jul 1994;192(1):1–10.PubMedGoogle Scholar
  209. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–819.PubMedCrossRefGoogle Scholar
  210. Thibodeau SN, French AJ, Roche PC et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. Nov 1 1996;56(21):4836–4840.PubMedGoogle Scholar
  211. Trojan J, Raedle J, Zeuzem S. [Germline mutations of the MSH6 gene in patients with an atypical hereditary nonpolyposis colorectal carcinoma (HNPCC)]. Z Gastroenterol. Jul 2000;38(7):607–609.PubMedCrossRefGoogle Scholar
  212. Ueda M, Toji E, Noda S. Germ line and somatic mutations of BRAF V599E in ovarian carcinoma. Int J Gynecol Cancer. Jul-Aug 2007;17(4):794–797.PubMedCrossRefGoogle Scholar
  213. Ueda H, Watanabe Y, Nakai H, Hemmi H, Koi M, Hoshiai H. Microsatellite status and immunohistochemical features of ovarian clear-cell carcinoma. Anticancer Res. Jul-Aug 2005;25(4):2785–2788.PubMedGoogle Scholar
  214. Umar A, Boyer JC, Thomas DC et al. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J Biol Chem. May 20 1994;269(20):14367–14370.PubMedGoogle Scholar
  215. Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. Feb 2004;4(2):153–158.PubMedCrossRefGoogle Scholar
  216. Vasen HF. Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer. 2005;4(3):219–225.PubMedCrossRefGoogle Scholar
  217. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. May 1991;34(5):424–425.PubMedCrossRefGoogle Scholar
  218. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. Jun 1999;116(6):1453–1456.PubMedCrossRefGoogle Scholar
  219. Vasen HF, Wijnen JT, Menko FH et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. Apr 1996;110(4):1020–1027.PubMedCrossRefGoogle Scholar
  220. Veigl ML, Kasturi L, Olechnowicz J et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA. Jul 21 1998;95(15):8698–8702.PubMedCrossRefGoogle Scholar
  221. Vessey MP, Painter R. Endometrial and ovarian cancer and oral contraceptives–findings in a large cohort study. Br J Cancer. Jun 1995;71(6):1340–1342.PubMedCrossRefGoogle Scholar
  222. Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968–2004. Br J Cancer. Aug 7 2006;95(3):385–389.PubMedCrossRefGoogle Scholar
  223. Wagner A, Hendriks Y, Meijers-Heijboer EJ et al. Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J Med Genet. May 2001;38(5):318–322.PubMedCrossRefGoogle Scholar
  224. Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg. Jul 2001;234(1):10–20.PubMedCrossRefGoogle Scholar
  225. Warthin A. Heredity with reference to carcinoma. Arch Intern Med. 1913;4:681–696.Google Scholar
  226. Warusavitarne J, Schnitzler M. The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. Jul 2007;22(7):739–748.PubMedCrossRefGoogle Scholar
  227. Watanabe T, Wu TT, Catalano PJ et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. Apr 19 2001;344(16):1196–1206.PubMedCrossRefGoogle Scholar
  228. Watson P, Butzow R, Lynch HT et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. Aug 2001;82(2):223–228.PubMedCrossRefGoogle Scholar
  229. Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993;71:677–685.PubMedCrossRefGoogle Scholar
  230. Watson P, Lynch HT. Cancer risk in mismatch repair gene mutation carriers. Fam Cancer. 2001;1(1):57–60.PubMedCrossRefGoogle Scholar
  231. Whiteman DC, Murphy MF, Cook LS et al. Multiple births and risk of epithelial ovarian cancer. J Natl Cancer Inst. Jul 19 2000;92(14):1172–1177.PubMedCrossRefGoogle Scholar
  232. Whittemore AS. Characteristics relating to ovarian cancer risk: implications for prevention and detection. Gynecol Oncol. 1994;55:S15–S19.PubMedCrossRefGoogle Scholar
  233. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. Nov 15 1992;136(10):1184–1203.PubMedGoogle Scholar
  234. Whittemore AS, Wu ML, Paffenbarger RS Jr. et al. Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am J Epidemiol. Dec 1988;128(6):1228–1240.PubMedGoogle Scholar
  235. Wijnen J, de Leeuw W, Vasen H et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. Oct 1999;23(2):142–144.PubMedCrossRefGoogle Scholar
  236. Willner J, Wurz K, Allison KH et al. Alternate molecular genetic pathways in ovarian carcinomas of common histological types. Hum Pathol. Apr 2007;38(4):607–613.PubMedCrossRefGoogle Scholar
  237. Woerner SM, Kloor M, von Knebel Doeberitz M, Gebert JF. Microsatellite instability in the development of DNA mismatch repair deficient tumors. Cancer Biomark. 2006;2(1–2):69–86.PubMedGoogle Scholar
  238. Worthley DL, Walsh MD, Barker M et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology. May 2005;128(5):1431–1436.PubMedCrossRefGoogle Scholar
  239. Wright CM, Dent OF, Barker M et al. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg. Sep 2000;87(9):1197–1202.PubMedCrossRefGoogle Scholar
  240. Wu Y, Berends MJ, Mensink RG et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. Nov 1999;65(5):1291–1298.PubMedCrossRefGoogle Scholar
  241. Wu AH, Shibata D, Yu MC, Lai MY, Ross RK. Dietary heterocyclic amines and microsatellite instability in colon adenocarcinomas. Carcinogenesis. Oct 2001;22(10):1681–1684.PubMedCrossRefGoogle Scholar
  242. Yamamoto H, Perez-Piteira J, Yoshida T et al. Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features. Gastroenterology. Jun 1999;116(6):1348–1357.PubMedCrossRefGoogle Scholar
  243. Yang P, Cunningham JM, Halling KC et al. Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers. Mol Genet Metab. Dec 2000;71(4):639–645.PubMedCrossRefGoogle Scholar

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© Springer Science+ Business Media, LLC 2010

Authors and Affiliations

  • Tuya Pal
    • 1
    Email author
  • Jenny Permuth Wey
    • 1
  • Thomas A. Sellers
    • 1
  1. 1.Department of Cancer Epidemiology and GeneticsMoffitt Cancer CenterTampaUSA

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