Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.

Yuqing Li,Kenneth B Beckman,Loïc Le Marchand,Daniel O Stram,Annette Lum-Jones,Remi Kazma,Christian Caberto,Iona Cheng,Christopher A Haiman,Richa Saxena,Anita Kloss-Brandstätter

doi:10.1371/journal.pone.0136796

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 (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19–2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups—African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.

Highlights

Colorectal cancer is the third most common cancer among men and women in the United States
In this study of 14,383 colorectal cancers (CRC) cases and controls, we comprehensively examined the contribution of the mitochondrial genome to CRC risk
Pathway analyses revealed that the mitochondrial genome and the oxidative phosphorylation pathway play a suggestive role in the CRC risk among European Americans

Summary

Introduction

Colorectal cancer is the third most common cancer among men and women in the United States. In 2015, an estimated 220,800 new colorectal cancers (CRC) were diagnosed in the United States [1]. Close to fifty risk loci for CRC have been identified by genome-wide association studies, which have focused on common variants of the nuclear genome [3,4,5,6,7]. These loci explain only a small proportion of the heritability of colorectal cancer and additional heritable factors remain to be discovered. This observation has been confirmed in many types of cancer cells that exhibit elevated levels of glucose transport and increased rates of glycolysis—referred to as the Warburg effect.[10, 11]

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Results

Conclusion