Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

被引:172
作者
Goodfellow, PJ
Buttin, BM
Herzog, TJ
Rader, JS
Gibb, RK
Swisher, E
Look, K
Walls, KC
Fan, MY
Mutch, DG
机构
[1] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA
[3] Univ Washington, Dept Obstet & Gynecol, Sch Med, Seattle, WA 98195 USA
[4] Indiana Univ, Med Ctr, Dept Obstet & Gynecol, Sch Med, Indianapolis, IN 46202 USA
[5] Washington Univ, Div Biostat, Sch Med, St Louis, MO 63110 USA
关键词
D O I
10.1073/pnas.1030231100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.
引用
收藏
页码:5908 / 5913
页数:6
相关论文
共 31 条
[1]  
Akiyama Y, 1997, CANCER RES, V57, P3920
[2]   Molecular and clinical characteristics of MSH6 variants:: An analysis of 25 index carriers of a germline variant [J].
Berends, MJW ;
Wu, Y ;
Sijmons, RH ;
Mensink, RGJ ;
van der Sluis, T ;
Hordijk-Hos, JM ;
de Vries, EGE ;
Hollema, H ;
Karrenbeld, A ;
Buys, CHCM ;
van der Zee, AGJ ;
Hofstra, RMW ;
Kleibeuker, JH .
AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (01) :26-37
[3]  
Boland CR, 1998, CANCER RES, V58, P5248
[4]   Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? [J].
Charames, GS ;
Millar, AL ;
Pal, T ;
Narod, S ;
Bapat, B .
HUMAN GENETICS, 2000, 107 (06) :623-629
[5]  
Charbonnier F, 2002, CANCER RES, V62, P848
[6]   Genotypic and phenotypic progression in endometrial tumorigenesis:: Determining when defects in DNA mismatch repair and KRAS2 occur [J].
Cohn, DE ;
Mutch, DG ;
Herzog, TJ ;
Rader, JS ;
Dintzis, SM ;
Gersell, DJ ;
Todd, CR ;
Goodfellow, PJ .
GENES CHROMOSOMES & CANCER, 2001, 32 (04) :295-301
[7]   The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas [J].
Cunningham, JM ;
Kim, CY ;
Christensen, ER ;
Tester, DJ ;
Parc, Y ;
Burgart, LJ ;
Halling, KC ;
McDonnell, SK ;
Schaid, DJ ;
Vockley, CW ;
Kubly, V ;
Nelson, H ;
Michels, VV ;
Thibodeau, SN .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (04) :780-790
[8]   ISOLATION OF AN HMSH2-P160 HETERODIMER THAT RESTORES DNA MISMATCH REPAIR TO TUMOR-CELLS [J].
DRUMMOND, JT ;
LI, GM ;
LONGLEY, MJ ;
MODRICH, P .
SCIENCE, 1995, 268 (5219) :1909-1912
[9]   hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis [J].
Esteller, M ;
Catasus, L ;
Matias-Guiu, X ;
Mutter, GL ;
Prat, J ;
Baylin, SB ;
Herman, JG .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (05) :1767-1772
[10]  
Gurin CC, 1999, CANCER RES, V59, P462