Abstract 945: Genetic association study of the mitochondrial genome and colorectal cancer risk: The Multiethnic Cohort
Authors: Cheng Iona C. , Caberto Christian , Beckman Kenneth , Lum-Jones Annette , Haiman Christopher , Marchand Loic L. , Stram Daniel , Saxena Richa 
Published: May 2015

Abstract
Background: The mitochondrial genome is highly specialized, encoding essential mitochondrial electron transport chain proteins required for aerobic metabolism, and involved in free radical production—two pathways that are involved in carcinogenesis. The role of the mitochondrial genome in colorectal cancer susceptibility has yet to be fully examined. We comprehensively characterized the genetic variation across the 16kb mitochondrial genome across five ancestral populations and examined the association between mitochondrial SNPs (mtSNPs) and colorectal cancer risk in a multiethnic population.
Methods: We compiled mitochondrial sequencing data from the public domain for African, Asian, European, and Latino populations, and sequenced the mitochondrial genomes of 160 Native Hawaiians. A total of 863 mtSNPs (MAF&gt;1%) were identified and genotyped in a multiethnic validation panel, identifying 621 mtSNPs with working assays and resulting in 446 mtSNPs detected in at least one sample. A total of 186 mtSNPs were prioritized based on MAF&gt;∼2% for genotyping in a case-control study of colorectal cancer nested in the Multiethnic Cohort (cases/controls=1,923/10,555). To evaluate the association between mtSNPs and colorectal cancer risk, odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusting for age, sex, and maternal self-reported ancestry. Stratified analysis were conducted by maternal self-reported ancestry given the wide variation in allele frequencies across ancestral groups. A Bonferroni-corrected p-value of 8.77x10-5 was used to determine statistical significance of associations given the number of mtSNPs tested and stratified analyses.
Results: At a nominal P&lt;0.05, 12 of 175 mtSNPs (MAF&gt;1%) were associated with colorectal cancer for all groups combined, while 5 of 114 mtSNPs, 1 of 45 mtSNPs, 7 of 65 mtSNPs, 42 of 101 mtSNPs, and 12 of 70 mtSNPs were associated among African Americans, Native Hawaiians, Asian Americans, Latinos, and European Americans, respectively. Statistically significant associations with colorectal cancer were observed with seven mtSNPs (four largely independent signals) among Latinos (P&lt;8.5x10-5). Among Latinos, the most significant association was observed with mt769 that is located within the gene that encodes for the 16s rRNA (OR=0.36; 95% CI: 0.23-0.55, P=5x10-6); this association remained statistically significant with adjustment for genetic ancestry based on nuclear DNA encoded ancestry informative markers.
Conclusion: Our study suggests that inherited variants of the mitochondrial genome may be associated with colorectal cancer risk in specific ancestral populations. Future work will further address population stratification of the mitochondrial genome, as well as investigate haplogroup associations and the cumulative effects of mitochondrial genes on colorectal cancer susceptibility.
Citation Format: Iona C. Cheng, Christian Caberto, Kenneth Beckman, Annette Lum-Jones, Christopher Haiman, Loic Le Marchand, Daniel Stram, Richa Saxena. Genetic association study of the mitochondrial genome and colorectal cancer risk: The Multiethnic Cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 945. doi:10.1158/1538-7445.AM2014-945