Dataset Information

No Association between the Mitochondrial Genome and Prostate Cancer Risk: The Multiethnic Cohort.

ABSTRACT: Mitochondria are involved in many processes that are central to the life and death of a cell. Oxidative phosphorylation (OXPHOS), in particular, is known to be altered in carcinogenesis, leading to an increase in the production of reactive oxidative species and glycolysis, one of the hallmarks of cancer cells. Because of this, genetic variation in the mitochondrial genome, which encodes for part of the OXPHOS pathway, has been suggested to play a role in many cancers, including prostate cancer.We comprehensively examined the role of the mitochondrial genome and prostate cancer risk in 4,086 prostate cancer cases and 3,698 controls from the Multiethnic Cohort (MEC), testing 350 mitochondrial SNPs (mtSNPs) in five racial/ethnic populations-Africans, Asian Americans, Europeans, Latinos, and Native Hawaiians. Logistic regression was conducted to examine single mitochondrial SNP and haplogroup associations. The sequence kernel association test was conducted for gene and pathway analysis.Eleven mtSNPs and haplogroup N were nominally associated with overall prostate cancer risk at P < 0.05. The mitochondrial DNA-encoded OXPHOS pathway, complexes, and genes were not associated with prostate cancer risk. No significant associations were identified after multiple testing corrections (all FDR q > 0.20).The mitochondrial genome was not associated with prostate cancer risk in our study of 7,784 subjects from the MEC.Our comprehensive study does not support the role of the mitochondrial genome in the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 1001-3. ©2016 AACR.

SUBMITTER: Giorgi EE

PROVIDER: S-EPMC4891274 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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No Association between the Mitochondrial Genome and Prostate Cancer Risk: The Multiethnic Cohort.

Giorgi Elena E EE Li Yuqing Y Caberto Christian P CP Beckman Kenneth B KB Lum-Jones Annette A Haiman Christopher A CA Le Marchand Loïc L Stram Daniel O DO Saxena Richa R Cheng Iona I

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20160328 6

<h4>Background</h4>Mitochondria are involved in many processes that are central to the life and death of a cell. Oxidative phosphorylation (OXPHOS), in particular, is known to be altered in carcinogenesis, leading to an increase in the production of reactive oxidative species and glycolysis, one of the hallmarks of cancer cells. Because of this, genetic variation in the mitochondrial genome, which encodes for part of the OXPHOS pathway, has been suggested to play a role in many cancers, includin ...[more]

PMID: 27021046

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Project description:BACKGROUND:The mitochondrial genome encodes for thirty-seven proteins, among them thirteen 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. METHODS:To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study. RESULTS:We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk. CONCLUSIONS:In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.

Project description: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.

Dataset Information

No Association between the Mitochondrial Genome and Prostate Cancer Risk: The Multiethnic Cohort.

Publications

No Association between the Mitochondrial Genome and Prostate Cancer Risk: The Multiethnic Cohort.

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