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

[1]  A. Jakubowska,et al.  A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland , 2007, Breast Cancer Research and Treatment.

[2]  G. Sa,et al.  The Regulation of S Phase Initiation by p27Kip1 in NIH3T3 Cells , 2005, Cell cycle.

[3]  J. Lubiński,et al.  CHEK2 is a multiorgan cancer susceptibility gene. , 2004, American journal of human genetics.

[4]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[5]  J. Lubiński,et al.  A novel founder CHEK2 mutation is associated with increased prostate cancer risk. , 2004, Cancer research.

[6]  J. Schleutker,et al.  CHEK2 variants associate with hereditary prostate cancer , 2003, British Journal of Cancer.

[7]  Carl D. Langefeld,et al.  Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage , 2003, Human Genetics.

[8]  A. Kibel,et al.  CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. , 2003, Cancer research.

[9]  J. Klijn,et al.  The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. , 2003, American journal of human genetics.

[10]  David I. Smith,et al.  Mutations in CHEK2 associated with prostate cancer risk. , 2003, American journal of human genetics.

[11]  O. Kallioniemi,et al.  A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. , 2002, American journal of human genetics.

[12]  Nazneen Rahman,et al.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002, Nature Genetics.

[13]  P. Pandolfi,et al.  Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse , 2001, Nature Genetics.

[14]  V. Kosma,et al.  Prognostic value and expression of p21(waf1/cip1) protein in prostate cancer , 1999, The Prostate.

[15]  J. Kato,et al.  Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1 , 1999, Nature.

[16]  C. Cordon-Cardo,et al.  Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. , 1999, Journal of the National Cancer Institute.

[17]  Y. Homma,et al.  Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. , 1998, Human pathology.

[18]  S. Groshen,et al.  Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. , 1998, Journal of the National Cancer Institute.

[19]  R. Weinberg,et al.  The Expanding Role of Cell Cycle Regulators , 1998, Science.

[20]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[21]  Cancer Epidemiol Biomarkers Prev , 2004 .

[22]  The Polish Breast Cancer Consortium.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002 .

[23]  HighWire Press,et al.  Cancer epidemiology biomarkers & prevention , 1991 .