Prevalence of somatic mutations in the breast cancer mitochondrial genome Free

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Mitochondrial mutations are common somatic events in breast cancer. It has been suggested that the extent of mitochondrial DNA (mtDNA) mutations affect prognosis and/or the response to certain therapies. In order to comprehensively investigate whether a high incidence of mutations exists in mtDNA of breast cancer tissues as well as to explore the association among mtDNA mutations, nuclear gene mutations and other tumor markers, namely p53 mutations and P16, ECAD. and RARB gene hypermethylation in 103 subjects with breast cancer. MtDNA mutations were determined by TTGE followed by sequencing. p53 mutations were determined by microarray analysis and hypermethylation was determined by real time PCR. The results showed that fifty-one (49.5%) tumors had somatic mtDNA mutations. Forty-two (40.78%) had mutations in the hypervariable D-loop region and 10 tumors (9.71%) had mutations in mRNA region. Mutation density analysis also showed that the D-loop region possesses significantly higher mutation density (6.73 mutation/10,000bps) when compared with other regions (tRNA 0.1159, rRNA 0.0626 and mRNA 0.1370). Twenty-two tumors had one mutation. Each of the remaining twenty-nine tumors had multiple somatic mutations with a total of 104 mutations. Among these mutations, eleven (10.6%) are short deletions or insertions, and the remaining 93 (89.4%) are point mutations. Some of these mutations are located in structurally/functionally important regions, e.g., missense mutations, at C4216T (H304Y) in ND1, G4769A(V100M) in ND2, and C8448T(T28M) in ATPase 8. Fifty-Seven (54.8%) mtDNA alterations were homoplasmic, twenty-seven (26%) were heteroplasmic in normal tissue and forty-seven (45.2%) were heteroplasmic in tumor tissue. Among the 67 distinct somatic mutations, 23 mutation positions were observed for the first time. Eight out of all 16 (50%) mRNA mutations are in the complex I gene. But the mutation density in this complex gene does not show significant difference when compared with other complex gene. We also found an insertion or deletion at the np303-309 poly C tract region in 9/103 (8.7%) tumors compared with 21%-72% in recent reports. There was no association with p53 mutational status or P16, ECAD, and RARB gene hypermethylations status. No significant correlation between mtDNA mutation and clinic-pathologic feature, such as tumor size, histologic grade, ploidy and S-phase value, has been found.

This study is among the largest to characterize the mtDNA mutational status. mtDNA somatic mutations in breast cancer can range from synonymous mutation, mild missense mutations, to severe insertion-deletions and are likely contribute to the initiation or progression of breast cancer. The heteroplasmic pattern is consistent with the hypothesis that these DNA alterations have taken place at the molecular level before the gross morphological change. [Supported by USAMR grant DAMD17-03-7-0446]