Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.
BACKGROUND
Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations of mismatch repair genes, usually in hMLH1 or hMSH2. All earlier studies on penetrance except one population based study were conducted in HNPCC families and did not correct for the way in which these families were ascertained.


OBJECTIVE
To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 genes.


METHODS
Families with known germline mutations of hMLH1 (n = 39) and hMSH2 (n = 45) were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for cancer of the colorectum and endometrium.


RESULTS
Both loci were analysed jointly as there was no significant difference in risk (p = 0.08). At age 70, colorectal cancer risk for men was 26.7% (95% confidence interval, 12.6% to 51.0%) and for women, 22.4% (10.6% to 43.8%); the risk for endometrial cancer was 31.5% (11.1% to 70.3%).


CONCLUSIONS
Current estimates of the CRC risk of mutations to the hMLH1 and hMSH2 locus should be replaced by considerably lower risks which account for the selection of the families.
Quehenberger
F
F
Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands.
Vasen
H F A
HF
van Houwelingen
H C
HC
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein