Abstract 221: Mitochondrial genome and the risk of lung cancer: The Multiethnic Cohort

Abstract

Abstract Background: The human mitochondrial genome (mtDNA) encodes for 13 essential polypeptides of the mitochondrial respiratory complex. Maternally-inherited variation in mtDNA may influence cancer development by altering mitochondrial proteins and complexes involved in the oxidative phosphorylation (OXPHOS) process. In lung cancer, Complex I appears frequently altered, which has been linked to increased cellular proliferation and invasion, and overproduction of reactive oxygen species. Few studies have investigated the associations between mtDNA variants and lung cancer risk. Methods: Within the 16 kb mtDNA, we tested 186 mitochondrial single nucleotide polymorphisms (mtSNPs) located in 13 genes that comprise the 4 complexes of the OXPHOS pathway and mtSNPs for rRNA and tRNA in 773 lung cancer cases and 10,491 controls from the Multiethnic Cohort. Logistic regression was conducted to examine the odds ratio (OR) and corresponding 95% confidence interval (CI) for mtSNPs and haplogroups associated with lung cancer risk. Associations were adjusted for age, sex, maternal self-reported race/ethnicity, principal components of global ancestry, smoking status, and the number of cigarettes smoked per day. The sequence kernel association test was conducted for pathway analysis, adjusting for the same covariates. Stratified analysis was conducted by self-reported maternal race/ethnicity—African American (AA), Japanese American (JA), Latino (LA), European American (EA), and Native Hawaiian (NH). Results: Overall, the most significant lung cancer association was seen with mt15629 (OR: 0.36, 95% CI: 0.22-0.60; p = 8×10-5 that reached a Bonferroni significance threshold of p = 2.7×10-4). This association was largely driven by AA (OR: 0.41, 95% CI: 0.24-0.71; p = 1.6×10-5; MAF = 0.05) and LA (OR: 0.14, 95% CI: 0.03-0.54; p = 4.8×10-5; MAF = 0.007) data with no evidence of heterogeneity in effects by race/ethnicity. Mt15629 was monomorphic in JA, EA, and NH populations. Similar patterns of associations were seen across histological cell types (small cell carcinoma, squamous cell carcinoma, and adenocarcinoma). Furthermore, mt15629 showed no evidence of heterogeneity in effects by smoking status and was not associated with smoking status or cigarette pack years. Haplogroup L1 was associated with lung cancer risk among LAs (OR: 0.14, 95% CI: 0.04-0.48; p = 0.002) for which mt15629 is one of the defining haplogroup mtSNPs. Pathway analysis showed an association between the cumulative effect of 161 polymorphic mtSNPs among LAs (p = 0.002); also the OXPHOS pathway (p = 0.002), 4 mitochondrial complexes (p = 0.001-0.049) and 10 of 15 mitochondrial genes (p = 0.001-0.049) were associated with lung cancer risk among LAs. Conclusion: Our findings demonstrate an association between specific variants in the mitochondrial genome and lung cancer risk, particularly among Latinos. The mechanism underlying this association appears to be independent of smoking status. Citation Format: Li Tao, Yuqing Li, Sung-Shim Lani Park, Kenneth B. Beckman, Christian Caberto, Annette Lum-Jones, Loic Le Marchand, Daniel O. Stram, Richa Saxena, Iona Cheng. Mitochondrial genome and the risk of lung cancer: The Multiethnic Cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 221.