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Epistatic Relationship between the Cancer Susceptibility Genes CHEK2 and p27

Cezary Cybulski¹, Bartomiej Gliniewicz¹, Andrzej Sikorski¹, Józef Kadny¹, Tomasz Huzarski¹, Jacek Gronwald¹, Tomasz Byrski¹, Tadeusz Dbniak¹, Bohdan Gorski¹, Anna Jakubowska¹, Dominika Wokolorczyk¹, Steven A. Narod² and Jan Lubiñski¹

¹ Pomeranian Medical University, Szczecin, Poland and ² Centre for Research on Women's Health, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Steven A. Narod, Centre for Research on Women's Health, University of Toronto, 790 Bay Street, Toronto, Ontario, Canada M5G IN8. Phone: 416-351-3765; Fax: 416-351-3767. E-mail: steven.narod{at}wchospital.ca

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)

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