Resident Physician Ohio State University Upper Arlington, Ohio, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Purpose: Mitochondria are maternally inherited organelles with a key role in processes associated with tumorigenesis such as metabolism. Mitochondrial DNA mutational burden (mtDNAB) had been previously suggested to be associated with a more aggressive clinical behavior in selected malignancies, yet a systemic assessment of its potential role as a prognostic marker across a variety of tumors of different tissue origin and various histologies had not been previously carried out to author’s knowledge. Moreover, its potential role as a marker of overall DNA aberrations load has not been explored. The purpose of this study was to assess the impact of mtDNAB on overall disease prognosis across eight different malignancies of various histological character.
Methodology: A total of 449 tumors representing a spectrum of malignancies (medulloblastoma n=69, pilocytic astrocytoma n=72, renal cell carcinoma n=24, hepatocellular carcinoma n=5, chronic lymphoblastic leukemia n=4, adenocarcinoma of the ovary n=60, prostate n=88, pancreas n=99 and endocrine pancreatic tumors n=29) with whole-exome sequencing data and clinical information publicly accessible were included in the study. Total mtDNAB was defined as the total count of mitochondrial mutations detected per tumor. Multivariate logistic regression analysis was carried out in R. Overall vital status (alive/deceased) was the dependent variable. The data was adjusted for treatment received.
Results: mtDNAB was negatively associated with overall prognosis (p=0.011.) There was no association between mtDNAB and tumor grade (p=0.05.) Additionally, mtDNAB was positively associated with High mtDNAB was noted in pancreatic endocrine tumors, renal cell carcinoma, ovarian and prostate adenocarcinoma. Additionally, mtDNAB was positively associated with the number of single nucleotide variants (both coding and non-coding) in individual tumors (p < 0.0001) but not multinucleotide variants, retrotransposon insertions, or chromosomal structural alterations (gains or losses of genomic material, p>0.05.) We did not observe an association with genetic ancestry.
Conclusions: Mitochondrial DNA mutational burden represents a potential negative prognostic marker in a variety of tumors. While the association between mitochondrial mutational burden and poor prognosis has been previously described in renal cell carcinoma (1), no previous reports show a direct association between mtDNAB and overall oncologic outcomes in pancreatic endocrine tumors, with sparse data in ovarian and prostate carcinoma. This finding warrants further exploration of mtDNAB's role as a potential biomarker in these malignancies. The positive association with SNVs is expected as mtDNA accumulates SNVs at approximately 10x higher rate compared to nuclear DNA (2); however, the absence of an association with additional DNA alterations suggests that the accumulation of mtDNAB within tumors is a process likely independent of nuclear genomic mutagenesis.
References: 1. Ricketts et al., 2018, Cell Reports 23, 313–326 April 3, 2018 2. Klink, G.V., O’Keefe, H., Gogna, A. et al. A broad comparative genomics approach to understanding the pathogenicity of Complex I mutations. Sci Rep 11, 19578 (2021).
