Abstract B61: Insights into lung cancer survival in African Americans from a study of germline variation in the microRNA network (2011)

Abstract Lung cancer remains one of the leading public health issues of our time. Moreover, it engenders prominent disparities in incidence and mortality across populations from diverse ethnic backgrounds. Specifically, African Americans, and particularly African American men, have an increased incidence and poorer survival from lung cancer compared to Caucasians. Previously, studies have looked at how populations differ in their susceptibility to lung cancer based on inheritance of deleterious or favorable alleles. However, germline variation in the microRNA network, and how it might contribute to racial disparities in lung cancer have not been studied to date. Using the NCI/UMD case control study, we collated a list of single nucleotide polymorphisms (SNPs) within the machinery that processes microRNA genes and subsequently guides them to their mRNA target transcripts. We then analyzed the association between these SNPs with lung cancer risk and survival in a Caucasian (n=567) and African American population (n=445). Associations with risk were determined using unconditional logistic regression adjusted for age, gender and smoking. Cox proportional hazards were used to compute hazard ratio estimates in a model adjusted for age, gender, stage and histology. A variant in the gene GEMIN3, a key partner in the complex that guides the microRNA to the mRNA strand was associated with an increased risk of lung cancer in African Americans, but not after adjustment for smoking status. However, the variant A allele was associated with adverse survival in an additive model in African Americans (HR AA vs. CC 2.27 [1.30–3.93] p=0.004). Notably, the association with risk was particularly prominent in late stage tumors (HR AA vs. CC 3.08 [1.72–5.54] p&amp;lt;0.001). Interestingly, no associations were seen in Caucasians, suggesting that this association is race-specific. In a follow up analysis, we observed that the deleterious AA genotype for GEMIN3 is present at 12% in African Americans, yet just 1% in Caucasians, perhaps in part explaining higher mortality rates in African Americans. Moreover, we analyzed a portion of these samples on which we had tumor tissue by microarray and observed that levels of GEMIN3 are significantly increased in tumor versus normal tissue from African Americans, but not Caucasians (fold enrichment 1.45, p=0.0015, FDR=0.014). This again suggests that GEMIN3 is somehow preferentially involved in lung cancer biology distinctly between the two populations. Further work is ongoing to study how this gene and indeed the variant allele of GEMIM3, contributes to poor survival in African Americans. The literature contains numerous examples of how tumor biology differs between individuals from various geographic areas, in part due to genetic heterogeneity and lifestyle. Understanding how these variations manifest and contribute to lung cancer pathogenesis will have novel insight for the rational and targeted treatment of tumors. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B61.