Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Abstract

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. (Cancer Epidemiol Biomarkers Prev 2007;16(3):572 -6)

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband

“…Both truncating and missense CHEK2 mutations predispose to prostate cancer (Cybulski et al, 2007c). One modifying gene has been proposed for prostate cancer; using this database, we have recently shown that the risk of prostate cancer depends on the genotype of p27 (Cybulski et al, 2007c).…”

“…One modifying gene has been proposed for prostate cancer; using this database, we have recently shown that the risk of prostate cancer depends on the genotype of p27 (Cybulski et al, 2007c). The excess risk of prostate cancer attributable to a CHEK2 mutation was restricted to carriers of the VV genotype at p27.…”

“…In all, 2007 patients with prostate cancer were interviewed from 1999 to 2007 at 13 centres situated throughout Poland. The cancer patients have been described in detail previously (Cybulski et al, 2004b;Cybulski et al, 2007c). The study was approved by the ethics board of the Pomeranian Medical University.…”

“…CHEK2 mutations predispose men and women to a range of cancer types, including breast, prostate and colon (Cybulski et al, 2004b;Cybulski et al, 2007b). For breast and prostate cancer, the truncating mutations are associated with higher penetrance than the missense mutation (Cybulski et al, 2007c). For colon cancer, only the missense variant I157T is associated with an elevated risk (Cybulski et al, 2007b).…”

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

“…Another way of considering this issue involves defining the temporal sequence of genetic lesions that drive oncogenesis, and thus to infer the sequential downstream interactive effect(s) of each lesion on other as-yet-unmutated regulatory genes. 69 Indeed, increasing evidence supports the importance of such epistatic processes for mammalian cancer development 24,[70][71][72][73] and, perhaps, also for transgenerational carcinogenesis. 6,74 The central finding of the present study is the unanticipated insight that the structural and functional attributes of GKs and POs-when compared with control subgroups of CT cancer suppressor genes and functionally unrelated but developmentally important HD genes-are strikingly similar, as indicated by congruences of evolutionary rate, expression level and breadth, gene length and methylation-dependent mutation confirmed by logistic regression and C-statistics.…”