Epistatic relationship between the cancer susceptibility genes CHEK2 and p27.
We studied the effects of p27 and CHEK2 variants on prostate and colon cancer risk in a case-control study. Modest effects on prostate cancer risk were observed for both CHEK2 missense and truncating variants. However, the excess cancer risk was restricted to the subgroup of men who were homozygous for the VV genotype in codon 109 of the p27 gene. Among men with the VV p27 genotype, the odds ratios associated with truncating and missense CHEK2 mutations were 3.1 (P < 0.0001) and 1.9 (P < 0.0001), respectively. Among men with other p27 genotypes (GG and VG), the odds ratios were 1.5 and 1.2 for truncating and missense CHEK2 mutations, respectively, and were not statistically significant. The interaction between CHEK2 and p27 was confirmed in a group of patients with colon cancer. Thus, it seems that the clinical expression of CHEK2 variant alleles on prostate and colon cancer risk may be restricted to individuals with a specific genotype (VV) of the p27 gene. Two-gene models provide numerous challenges for gene identification and cancer risk assessment.
Cybulski
Cezary
C
Pomeranian Medical University, Szczecin, Poland.
Gliniewicz
Bartłomiej
B
Sikorski
Andrzej
A
Kładny
Józef
J
Huzarski
Tomasz
T
Gronwald
Jacek
J
Byrski
Tomasz
T
Debniak
Tadeusz
T
Gorski
Bohdan
B
Jakubowska
Anna
A
Wokolorczyk
Dominika
D
Narod
Steven A
SA
Lubiñski
Jan
J
D000368:Aged; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases