RNA-Seq to reveal mitochondrial gene fusions in breast cancer.

Abstract

e13019 Background: Several mitochondrial DNA (mtDNA) mutations have been identified in various types of human cancer. While gene fusions encoded by the nuclear genome have an important role in tumorigenesis, the contribution of the mitochondrial genome to this process is unclear. mtDNA has limited protective mechanisms compared to that for nuclear DNA (nDNA), and hence more susceptible to genomic aberrations. Methods: We sequenced RNA from pre and post treatment breast cancer samples obtained from neoadjuvant clinical trials BrUOG 211A/211B. Seventy-three of these samples were considered baseline and 61 were from post-treatment samples, 54 samples at both time points. Patients were given a run-in dose of bevacizumab (B), nab- paclitaxel (N) or trastuzumab (T), followed by combination biologic/chemotherapy (HER2- with B/carboplatin/N; HER2+ with T/carboplatin/N). RNA was derived from biopsy pairs obtained pre/post 10-day exposure to run-in monotherapy. We used TopHat-Fusion and deFuse for fusion detection. Results: On average, in each patient 4.6 mtDNA gene fusions were detected at the baseline and 4 in the post treatment samples. In this cohort we detected in total 385 mtDNA fusions across the baseline and 344 across the post-treatment samples. A number of fusions had recurrently shown drastic increase from baseline to post-treatment, such as MT-ATP6:MT-ND2 ( N = 9), MT-ND6:MT-CO2 ( N = 6), MT-ND6:MT-CO1 ( N = 10), and MT-ND4:MT-ATP6 ( N = 9). We observe that some mitochondrial genes such as MT-ND6 have as many as 7 gene partners. MT-ND6 appeared in fusions that were most abundant among both baseline and post-treatment samples with MT:ND4 ( N = 39), MT:ND2 ( N = 37) and MD:ATP6 ( N = 36). Interestingly, gene fusions MT-ND6:J01415.25, MT-CYB:MT-ND2 and MT-ND6:MT-ND1 were observed respectively in 9, 5 and 4 baseline samples but not in their post treatment equivalent. Conclusions: While several studies have examined the presence of mtDNA mutations in breast cancer, the role of mitochondrial gene fusions is unknown in cancer. In our breast cancer cohort we observed quite a high number of mitochondrial fusions, and some of them seem to be recurrent in multiple samples. This could potentially have clinical implications as knowledge of fusions in solid tumours gains.