Abstract
Studies have suggested a potential role of somatic mitochondrial mutations in cancer development. To analyze the landscape of somatic mitochondrial mutation in breast cancer and to determine whether mitochondrial DNA (mtDNA) mutational burden is correlated with overall survival (OS), we sequenced whole mtDNA from 92 matched-paired primary breast tumors and peripheral blood. A total of 324 germline variants and 173 somatic mutations were found in the tumors. The most common germline allele was 663G (12S), showing lower heteroplasmy levels in peripheral blood lymphocytes than in their matched tumors, even reaching homoplasmic status in several cases. The heteroplasmy load was higher in tumors than in their paired normal tissues. Somatic mtDNA mutations were found in 73.9% of breast tumors; 59% of these mutations were located in the coding region (66.7% non-synonymous and 33.3% synonymous). Although the CO1 gene presented the highest number of mutations, tRNA genes (T,C, and W), rRNA 12S, and CO1 and ATP6 exhibited the highest mutation rates. No specific mtDNA mutational profile was associated with molecular subtypes of breast cancer, and we found no correlation between mtDNA mutational burden and OS. Future investigations will provide insight into the molecular mechanisms through which mtDNA mutations and heteroplasmy shifting contribute to breast cancer development.
Highlights
Breast cancer is the most common cancer type in women worldwide [1]; in 2018, 2.09 million cases and 627,000 deaths were estimated around the world [2]
Stratification analysis by IHC subtypes revealed that haplogroups C and D were present only in luminal A (LA) and luminal B (LB) subtypes, and triple negative (TN) tumors carried haplogroups A and B
The mitochondrial genome function is relevant for the transformation processes; tumor cells are able to escape from different regulatory mechanisms, but they cannot evade energy flow mechanisms
Summary
Breast cancer is the most common cancer type in women worldwide [1]; in 2018, 2.09 million cases and 627,000 deaths were estimated around the world [2]. In Mexico, this malignancy is currently the leading cause of cancer-related deaths in women [3,4,5]. Breast cancer is a heterogeneous disease in terms of the molecular features and clinical outcome; knowledge of the genetic causes is still incomplete. To comprehensively address this issue, the analysis of nuclear genes has been frequently done [4, 6,7,8,9,10]. Mutations in mitochondrial genes have been reported to play important roles in human cancer development [11]. Experimental evidence in mouse models demonstrated that G13997A and 13885insC mutations in the reduced form of the nicotinamide adenine dinucleotide dehydrogenase subunit 6 (ND6) gene are associated with the transition of poor metastatic tumor cells into a highly metastatic phenotype [12]
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