Low allele frequency of MLH1 D132H in American colorectal and endometrial cancer patients.
OBJECTIVE
Hereditary nonpolyposis colon cancer is caused by mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2. Classic MLH1 mutations cause an approximately 20-fold increase in colorectal cancer susceptibility. Recently, we identified a hypomorphic allele, MLH1 D132H , which impairs, but does not completely eliminate the function of MLH1 in tumor suppression. MLH1 D132H confers an approximately fivefold increase in colorectal cancer susceptibility and was first described in a cohort of Israeli colorectal cancer patients, with an estimated allele frequency of 1.3 percent. Because MLH1 D132H has only recently been described, the ethnic distribution of this risk allele is not well understood. This study was undertaken to determine both the frequencies of this risk allele in ethnic groups outside of Israel and whether families harboring this mutation have susceptibility to extracolonic cancers in the hereditary nonpolyposis colon cancer spectrum.


METHODS
We genotyped two independent cohorts: 629 population-based colorectal cancer patients ascertained from clinics in Orange, Imperial, and San Diego Counties, and 515 endometrial cancer patients ascertained from gynecologic oncology clinics in the Midwestern United States.


RESULTS
MLH1 D132H was not detected in either study cohort, which together totaled more than 1,100 American colorectal cancer and endometrial cancer patients.


CONCLUSIONS
The MLH1 D132H risk variant has significantly lower allele frequency in American compared with Israeli cancer patients and, alone, is unlikely to explain significant amounts of American sporadic colorectal cancer or uterine cancer susceptibility. Genetic testing for the MLH1 D132H allele exclusively is therefore unlikely to be cost effective for genetic risk assessment in American population-based and clinic-based colorectal cancer and endometrial cancer patients.
Shin
Brian Y
BY
Division of Hematology/Oncology, Department of Medicine, University of California Irvine, 92697, USA.
Chen
Huiping
H
Rozek
Laura S
LS
Paxton
Leslie
L
Peel
David J
DJ
Anton-Culver
Hoda
H
Rennert
Gad
G
Mutch
David G
DG
Goodfellow
Paul J
PJ
Gruber
Stephen B
SB
Lipkin
Steve M
SM
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D014481:United States
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1