Abstract 3806: Mitochondrial DNA (MtDNA) analysis in colorectal neoplasia

Abstract

Abstract PURPOSE: Colorectal cancer is the third most common cause of cancer-related deaths in both men and women in the western hemisphere. The prognosis is based on the stage of tumor at the time of diagnosis, with surgery being the most effective treatment; beginning at distinct adenomatous stages- tubular, tubulovillous, and villous, to carcinoma. The best evaluation of colorectal tumor progression, especially the early adenomas, continues to confound clinicians and the presence of colorectal adenomas dysplasia subtype, increases one's risk of developing colorectal cancer. The overall objective of this study was to evaluate mtDNA variants in three stages of colorectal adenomatous polyps; Tubular (T), Tubulovillous, (TV), Villous (V) adenomas, and Cancer (C). DESIGN METHODS: PCR-based sequencing and High resolution endonucleases were used to detect mtDNA variants in 1.8 kb of ATP 6 and 8, 2.2 kb of Complex 1 ND5 and 2.6 Complex 1 MT-ND4 of Cytochrome B genes from 64 clinicopathological colorectal adenomatous polyps; T, TV, V, Cancer, and their paracancerous/normal surrounding tissue (NST) that were obtained from Cooperative Human Tissues Network and Grady Memorial Hospital, Atlanta, Georgia. HYPOTHESIS: Our hypothesis is that alterations in the mitochondrial genome of early colorectal tumors compared to non-cancerous, normal surrounding, tissue will allow us to identify a profile of polymorphisms worthy of follow-up investigation as candidate for early colorectal cancer morphological and stage-specific markers. RESULTS: Thirty-nine of mtDNA variants were detected with primers spanning 1.8 kb of ATP 6 and 8 regions, of which 25 (64%) were previously unreported based on the MITODAT reference database. Twenty four of 39 (62%) mtDNA variants were somatic mutations. Notably, three germ-line variants; G8407C, G8680C, and G8681 were observed in tubular adenomas only and four somatic variants; 8714delC, 8766delC, 8668delC and 8670delA were observed in villous adenomas. With primers spanning 2.2 kb of Complex 1 ND5 and 2.6 Complex 1 MT-ND4 of Cytochrome B genes, 104 mtDNA variants were detected of which 6 (5%) were previously reported based on the MITODAT reference database. Ninety-nine of 104 (95%) mtDNA variants were unreported mutations. Two germ-line variants; G11914A, T11944C were observed in tubulovillous adenomas; 10 somatic variants were observed in tubular adenomas; 42 somatic variants were observed in villous; and all other mutations were an insertion or deletion of base pairs in all polyp types and/or cancer. CONCLUSION: Our current data provide a basis for continued investigation of certain mtDNA variants as potential genetic biomarkers for colorectal adenomatous polyps in a larger number of clinicopathological tissue specimens, and other regions of the mt genome. Research supported by NIH-NCI Grant # CA150317-01A2 and Grant # CA150039-01 awarded to Felix O. Aikhionbare at Morehouse School of Medicine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3806. doi:10.1158/1538-7445.AM2011-3806