Abstract 2217: Analysis of mitochondrial variations in non-small cell lung cancer (NSCLC) by microarray-based genome resequencing

Abstract

Abstract The human mitochondrial genome is a circular double-stranded DNA molecule (mtDNA) of 16,569 base pairs, encoding 13 proteins that are essential in oxidative phosphorylation, two ribosomal genes, and 22 tRNAs. The mtDNA genome has a high copy number per cell, replicates independently of the nuclear genome, and has a maternal-inherited pattern. Mutations in mtDNA genome have long been suspected to play an important role in the development of cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of cancer remains unclear. In this study, we resequenced the entire mitochondrial genomes of tumor tissue from a population of 249 Korean non-small cell lung cancer (NSCLC) patients using the Affymetrix GeneChips Human Mitochondrial Resequencing Array 2.0 (Santa Clara, CA). A total of 892 single nucleotide polymorphisms (SNPs) were identified, including 269 (30.2%) synonymous SNPs, 142 (15.9%) non-synonymous SNPs, 78 (8.7%) SNPs in non-coding region, 188 SNPs (21.1%) in control region, as well as 215 (24.1%) previously unreported SNPs. Each tumor sample contained at least 6 mitochondrial SNPs, with maximum 41 SNPs. We selected 189 (21.2%) SNPs with frequency >2.5% for subsequent analyses. Single SNP analysis using Cox proportional hazards models identified 19 SNPs with p value < 0.05, but none of them remained significant after adjustment for multiple comparisons. Unsupervised clustering analysis revealed two major SNP signature panels, including Signature Panel 1 (8 SNPs) and Signature Panel 2 (5 SNPs). Accordingly, the patient population was divided into three groups: 68 (27.3%) subjects with both signature panels, 73 (29.3%) subjects with only the Signature Panel 1 but not the Signature Panel 2, and 108 (43.4%) subjects without signature panel. In early stage (stage I/ II) NSCLC, patients with the Signature Panel 2 had the worst clinical prognosis, and patients without any signature panel performed best in the survival analyses (adjust hazard ratio=1.83; 95% confidence interval, 1.25-2.66; p=0.003). Further mitochondrial haplogroup analysis identified that the Signature Panel 1 had most defining mutations for haplogroup M and N, and the Signature Panel 2 contained all defining mutations of haplogroup D4a. Interestingly, haplogroup D4a was previous reported as a marker for extreme longevity in Japanese. We conclude that mtDNA mutations may play an important role in survival among early stage lung cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2217.