Abstract 2749: Mitochondrial DNA variants independently predict survival in invasive breast cancer: Results from the Carolina Breast Cancer Study

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background Mitochondria possess a distinct DNA genome (mtDNA) that encodes proteins of critical importance to cellular energy metabolism, free radical production, and apoptosis. These processes are central to cancer-cell proliferation, angiogenesis, and metastasis, as well as to treatment response; hence, the rich variation present in mtDNA may impact cancer prognosis. We previously reported the association of mtDNA variant G10398A with risk of invasive breast cancer (BC) in African American (AA) women from the Carolina Breast Cancer Study (CBCS), a large, population-based BC case control study. This study evaluated the role of two homoplasmic, mtDNA germline variants, G10398A and T4216C, on BC outcome. Methods The CBCS enrolled 1,557 women with incident, primary invasive BC, aged 20-74, between 1993 and 2001 (Phases I and II). In-person interviews were conducted to collect a blood sample and ascertain demographic, lifestyle, and risk-factor information; tumor histology and clinical data were confirmed by pathology and medical-chart review, respectively. Median active follow-up of enrolled BC cases is currently >10 years. G10398A and T4216C genotypes were determined from blood-derived genomic DNA, using a fluorogenic 5’ nuclease allelic discrimination TaqMan PCR assay. Stratified Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (95% CIs) for associations of mtDNA variants with BC-specific mortality, adjusting for potential confounders. Results Genotyping was successful at both mtDNA loci in >98% of subjects. Survival in the cohort overall was significantly superior among women with the 4216C allele compared to 4216T (HR 0.55; 95% CI 0.36-0.83, P<0.01) adjusting for age, race, and tumor stage (I-IV). Women with 4216C and 10398A alleles had the highest survival (adjusted HR 0.27, compared to the 4216T/10398G haplotype; 95% CI 0.11-0.67, P<0.01). The same prognostic pattern was noted in white women (N=899): HR 0.46 for 4216C vs. T (95% CI 0.28-0.77, P<0.01), adjusting for age and tumor stage; adjusted HR 0.26 for 4216C+10398A vs. T+G haplotype (95% CI 0.09-0.80, P<0.05). Similar but statistically insignificant results were observed in 658 AA cases. Finally, although T4216C and T4216C/G10398A genotypes correlated with tumor hormone-expression status and subtypes, and G10398A genotype also correlated with tumor stage and mitotic index (P<0.05 for all), the 4216C allele and 4216C/10398A haplotype remained independently predictive of survival even after adjustment for recognized prognostic factors. Conclusions These findings, which require replication in other cohorts, suggest that mtDNA variant T4216C, together with G10398A, carries significant, independent prognostic impact in BC and that the role of mtDNA germline variants should be comprehensively explored in BC outcomes. 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 2749. doi:10.1158/1538-7445.AM2011-2749