MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer.
Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (-93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 -93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 -93G>A polymorphism defines a low penetrance risk allele for CRC.
Allan
James M
JM
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. james.allan@newcastle.ac.uk
Shorto
Jennifer
J
Adlard
Julian
J
Bury
Jonathan
J
Coggins
Ron
R
George
Rina
R
Katory
Mark
M
Quirke
Philip
P
Richman
Susan
S
Scott
Daniel
D
Scott
Kathryn
K
Seymour
Matthew
M
Travis
Lois B
LB
Worrillow
Lisa J
LJ
Bishop
D Timothy
DT
Cox
Angela
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D020137:Base Pair Mismatch; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D004260:DNA Repair; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1