Abstract
Mismatch repair (MMR) gene mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), a common form of familial colorectal cancer. Among MMR genes, germline MSH6 mutations are often observed in HNPCC-like families with an increased frequency of endometrial cancer. We have previously shown that a proportion of women affected with double primary cancers of the colorectum and endometrium carry germline MSH2 or MLH1 mutations and, thus, belong to HNPCC families. In this study, we have investigated the specific contribution of MSH6 defects to such double primary patients. By sequence analysis of the entire coding region of MSH6, three putative missense mutations were identified in patients with atypical family histories that do not meet HNPCC criteria. Moreover, one of these mutations, a novel substitution Arg901His, was found in a patient previously shown to carry a truncating germline MLH1 mutation. Thus, MSH6 mutations are likely to contribute to the etiology of double primary cancers of the colorectum and endometrium.
Similar content being viewed by others
References
Aarino M, Mecklin J-P, Aaltonen L, Nyström-Lahti M, Jarvinen HJ (1995) Lifetime risk of different cancers in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64: 430–433
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani N, Srivastava S (1998) 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 58: 5248–5257
Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B (1997) Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6: 106–110
Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185: 862–864
Iaccarino I, Marra G, Dufner P, Jiricny J (2000) Mutation in the magnesium binding site of hMSH6 disables the hMutSα sliding clamp from translocating along DNA. J Biol Chem 275: 2080–2086
Jiricny J, Nyström-Lahti M (2000) Mismatch repair defects in cancer. Curr Opin Genet Dev 10: 157–161
Johnson RE, Kovvali GK, Prakash L, Prakash S (1996) Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. J Biol Chem 271: 7285–7288
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessop JM, Kolodner R (1997) 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 57: 808–811
Marsischky GT, Filosi N, Kane MF, Kolodner R (1996) Redundancy of Sacchromyces cerevisiae MSH3 and MSH6 in MSH2- dependent mismatch repair. Genes Dev 10: 407–420
Mecklin JP, Jarvinen HJ (1991) Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 68: 1109–1112
Millar AL, Pal T, Madlensky L, Sherman C, Temple L, Mitri A, Cheng H, Marcus V, Gallinger S, Redston M, Bapat B, Narod S (1999) Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. Hum Mol Genet 8: 823–829
Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T (1997) Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17: 271–272
Pal T, Flanders T, Mitchell-Lehman M, MacMillan A, Brunet J-S, Narod SA, Foulkes WD (1998) Genetic implications of double primary cancers of the colorectum and endometrium. J Med Genet 35: 978–984
Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D’Arrigo A, Truong O, Hsuan JJ, Jiricny J (1995) GTBP, a 160kilodalton protein essential for mismatch-binding activity in human cells. Science 268: 1912–1914
Papadopolous N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D’Arrigo A, Markowitz S, Willson JKV, Kinzler KW, Jiricny J, Vogelstein B (1995) Mutations of GTBP in genetically unstable cells. Science 268: 1915–1917
Parc YR, Halling KC, Wang L, Christensen ER, Cunningham JM, French AJ, Burgart LJ, Price-Troska TL, Roche PC, Thibodeau SN (2000) hMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60: 2225–2231
Plaschke J, Kruppa C, Tischler R, Bocker T, Pistorius S, Dralle H, Richoff J, Saeger HD, Fishel R, Schackert HK (2000) Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer. Int J Cancer 85: 606–613
Service RF (1994) Stalking the start of colon cancer. Science 263: 1559–1560
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260: 816–819
Vasen HFA, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard ML, Mohr J, Fodde R, Khan PM (1996) Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110: 1020–1027
Vasen HFA, Watson P, Mecklin J-P, Lynch HT, ICG-HNPCC (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116: 1453–1456
Watson P, Lynch HT (1993) Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71: 677–685
Wijnen J, de Leeuw W, Vasen H, van der Klift H, Möller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Möslein G, Tops C, Briker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R (1999) Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23: 142–144
Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM (1999) Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 65: 1291–1298
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Charames, G.S., Millar, A.L., Pal, T. et al. Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium?. Hum Genet 107, 623–629 (2000). https://doi.org/10.1007/s004390000417
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s004390000417