Abstract 4589: Association of genes, pathways, and haplogroups of the mitochondrial genome with the risk of colorectal cancer: The Multiethnic Cohort

Abstract

Abstract The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer risk, we tested 185 mitochondrial SNPs (mtSNPs) located in 13 genes that comprise the four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, among 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort. Using the SNP-set kernel-machine association test, we analyzed the collective set of 185 mtSNPs and subsets grouped by mitochondrial pathways, complexes, or genes, adjusting for age, sex, and principal components of global ancestry. We also tested for haplogroup associations, adjusting for the same covariates. Since the mitochondrial genome is maternally inherited and exhibits wide variation in allele frequencies across ancestral populations, we conducted stratified analyses by self-reported maternal race/ethnicity (African American, Asian American, European American, Latino and Native Hawaiian). Collectively, the 185 mtSNPs of the mitochondrial genome were associated with colorectal cancer among European Americans (p = 0.04). The OXPHOS pathway (p = 0.029, SNPs = 133) and Complex I (p = 0.025, SNPs = 80) and Complex III (p = 0.027, SNPs = 15) within this pathway were associated with colorectal cancer risk among European Americans. The NADH-ubiquinone oxidoreductase chain 2 (ND2) in Complex I was associated with colorectal cancer risk at a nominal p-value of 0.001 in European Americans, but did not reach a stringent Bonferroni corrected significance threshold of 0.0007 (72 genes observed across the five racial/ethnic groups). Haplogroup T was associated with colorectal cancer risk among European Americans (OR = 1.66, 95% CI: 1.19-2.33, p = 0.0003; reaching a Bonferroni corrected alpha of 0.001). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups. In summary, our findings suggest that the mitochondrial genome may play a role in colorectal cancer risk among European Americans, particularly among those carrying the haplogroup T. Replication and evaluation of the OXPHOS pathway encoded by both the nuclear and mitochondrial genomes is warranted. Citation Format: Yuqing Li, Kenneth Beckman, Christian Caberto, Remi Kazma, Annette Lum-Jones, Christopher A. Haiman, Loic Le Marchand, Daniel O. Stram, Richa Saxena, Iona Cheng. Association of genes, pathways, and haplogroups of the mitochondrial genome with the risk of colorectal cancer: The Multiethnic Cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2015-4589