Abstract 1171: From genotypes to phenotypes: genetic variation in microRNA-related genes and lung cancer risk

Abstract

Abstract Differential microRNA expression and function has been implicated in a variety of human malignancies. Genetic variation in this network was recently proposed to explain the contribution of this family of non-coding RNAs to cancer. To test this hypothesis in lung cancer in a systematic manner, we collated a list of single nucleotide polymorphisms (SNPs) that lie within pre and mature miRNA genes. We then generated a list of SNPs from 600 genes in loci and pathways with relevance to lung cancer. The 3’ UTR of each of these genes was bioinformatically interrogated for overlap between putative microRNA binding sites and SNPs. The latter could either create or destroy a microRNA binding site and therefore impact protein translation. The SNPs were subsequently analyzed in a study of 300 Caucasian cases and 300 controls. Odds ratios for lung cancer risk were generated using unconditional logistic analyses and adjusted for age, gender, race, smoking status and pack years of smoking. Our study highlighted a number of novel associations. From our inflammation panel of genes, a SNP in the 3’ UTR of CXCR2 (IL8 receptor) was protective against lung cancer risk (OR: 0.44; 95% C.I. 0.26 – 0.78). As CXCR2 is implicated in oncogene induced senescence, we predict that this SNP gives rise to lower levels of the receptor and are currently testing this possibility both in vitro and in human tissues. Furthermore, a SNP in DRD1 (dopamine receptor DI) is also protective against lung cancer (OR: 0.45; 95% C.I. 0.24 – 0.85), thus intimating that the variant allele gives rise to decreased levels of DRD1 in the brain and therefore a negative re-enforcement of the reward pathway. Several metabolic genes were implicated from our study, the most notable of which was a SNP in ALDH1A3 (OR: 1.79; 95% C.I. 1.01 – 3.17). Apart from the delineated role in metabolism, this gene is also interesting due to its putative role in lung cancer stem cell biology. Although SNPs in microRNA genes are generally rare, a SNP in miR-585 was significantly associated with an increased risk of lung cancer (OR: 1.69; 95% C.I. 1.10 – 2.59), and most interestingly, the association was strongest for heterozygous carriers. We are currently investigating the effect of the miR-585 SNP on expression of the mature miRNA as well as the role of miR-585 in lung cancer etiology, as nothing is known in this regard at present. This study is presently being extended to a cohort of African American patients and a nested analysis of never-smokers is also underway. Moreover, we are endeavoring to determine the functional consequences of these epidemiological results and link risk-associated genotypes to oncogenic phenotypes. Our data provides a comprehensive evaluation of the association between genetic variation in the microRNA network and lung cancer risk, and has highlighted several novel associations that may help in our understanding of the genetic basis of lung cancer and the role that microRNAs play. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1171. doi:10.1158/1538-7445.AM2011-1171