Abstract LB-409: Opposing effect of CHEK2 mutations for lung and kidney cancer: a meta analysis

Abstract

Abstract Rare variants in CHEK2, checkpoint kinase 2, cell cycle control gene have been associated with various cancer sites including breast, prostate and colon cancer. Previously, two independent studies indicated a strong protective effect of CHEK2 mutations on the risk of lung and aero-digestive cancer but not kidney cancers (Brennan et al., 2007; Cybulski et al., 2008). We have conducted an independent case-control study to replicate these observed effects. 1202 cancer free controls, 481 individuals with primary lung cancer and 252 primary kidney cancer cases, all of Russian origin, were included in the study. All individuals were genotyped for the I157T variant (rs17879961) using Taqman. We also genotyped samples from the study published by Brennan et al. (2007) for three additional rare mutations found to be present in the central and eastern European population (1100delC, IVS2+1G>A and the deletion of 5Kb (across exons 12 and 14)). We used logistic regression techniques to calculate odds ratios (ORs) and 95% confidence interval (95%CIs), adjusted for age, gender and pack-years of tobacco smoking. We additionally performed a meta-analysis of central and eastern European studies investigating lung and kidney cancer and CHEK2 mutations. Based on new data, the I157T rare variant showed a similar trend as in previous studies (OR = 0.78, 95%CI 0.43-1.40 for lung cancer and OR= 1.30, 95%CI 0.75-2.26 for kidney cancer). The combined OR for all three studies based on a fixed effects model indicated a strong protective effect of the CHEK2 I157T rare variant on the risk of lung cancer with OR of 0.43 (95%CI 0.35-0.53). The effect was stronger for squamous cell carcinoma (OR=0.21, 95%CI 0.12-0.37) and non significant for adenocarcinoma (OR=0.90, 95%CI 0.61-1.34). Results of meta-analysis on kidney cancer confirmed the previously observed increased risk effect of the CHEK2 I157T mutation with an OR of 1.38 (95%CI 1.04-1.82). Similar effects were observed for the combination of all mutations. Furthermore, haplotype analysis indicates that each mutation is characterized by unique extended haplotype consistent with the notion of a founder effect. The present study and performed meta-analysis confirmed previous opposing results for the effects of CHEK2 mutations on the risk of lung and kidney cancer. The mechanism for these inverse effects is unknown. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-409.