Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 99, Issue 5, Pages 697-704Publisher
WILEY-LISS
DOI: 10.1002/ijc.10429
Keywords
endometrial cancer; mismatch repair; tumor MSI; familial risk for cancer
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Funding
- NCI NIH HHS [CA71754] Funding Source: Medline
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Loss of DNA mismatch repair occurs in a variety of malignancies and is associated with genome-wide instability of microsatellite repeats, a molecular phenotype referred to as microsatellite instability (MSI). MSI is a consistent feature of colorectal and endometrial tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC). Sporadic colorectal and endometrial cancers that exhibit MSI frequently have methylation of the MLHI promoter. We undertook a detailed family and medical history study to compare family cancer risk for women with MSI-positive and -negative endometrial cancers. The MLHI promoter methylation status was determined for all cancers. Family histories were developed for 80 probands (40 with MSI-positive and 40 with MSI-negative tumors). The numbers of reported cancers in first- and second-degree relatives of the 2 groups were similar. There was a modest increase in familial cancer clustering for MSI-positive probands. When MSI-positive tumors were subclassified according to MLHI promoter methylation, a clear association between methylation status and familial cancer risk was evident. Women with MSI-positive endometrial cancers in which the MLHI promoter was unmethylated had a 7-fold relative risk. (RR) of demonstrating familial clustering of cancers [RR 7.07 (95% confidence interval 2.29-21.81)]. The women with MSI-positive, MLHI-unmethylated tumors were significantly younger than the rest of the study population (56.1 years vs. 65.4, p less than or equal to 0.01). Age of onset and tumor MSI not associated with MLH I promoter methylation may point to women with a genetic susceptibility to malignancies. (C) 2002 Wiley-Liss, Inc.
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