Oncotarget

Research Papers:

Sequence conservation of mitochondrial (mt)DNA during expansion of clonal mammary epithelial populations suggests a common mtDNA template in CzechII mice

Jabril R. Johnson, Justin B. Lack, Corinne A. Boulanger, Lauren E. Ragle and Gilbert H. Smith _

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Oncotarget. 2020; 11:161-174. https://doi.org/10.18632/oncotarget.27429

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Abstract

Jabril R. Johnson1,3, Justin B. Lack2, Corinne A. Boulanger1, Lauren E. Ragle1 and Gilbert H. Smith1

1 Mammary Stem Cell Biology Section, National Cancer Institute, Bethesda, MD 20892, USA

2 Bioinformatics Manager/Lead, NIAID Collaborative Bioinformatics Resource (NCBR) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Bethesda, MD 20894, USA

3 Department of Population Sciences, City of Hope, Duarte, CA 91107, USA

Correspondence to:

Gilbert H. Smith,email: smithg@mail.nih.gov

Keywords: mitochondrial DNA; next-generation sequencing; clonal expansion; mammary cancer

Received: November 08, 2019     Accepted: December 21, 2019     Published: January 14, 2020

ABSTRACT

One major foundation of cancer etiology is the process of clonal expansion. The mechanisms underlying the complex process of a single cell leading to a clonal dominant tumor, are poorly understood. Our study aims to analyze mitochondrial DNA (mtDNA) for somatic single nucleotide polymorphisms (SNPs) variants, to determine if they are conserved throughout clonal expansion in mammary tissues and tumors. To test this hypothesis, we took advantage of a mouse mammary tumor virus (MMTV)-infected mouse model (CzechII). CzechII mouse mtDNA was extracted, from snap-frozen normal, hyperplastic, and tumor mammary epithelial outgrowth fragments. Next generation deep sequencing was used to determine if mtDNA “de novo” SNP variants are conserved during serial transplantation of both normal and neoplastic mammary clones. Our results support the conclusion that mtDNA “de novo” SNP variants are selected for and maintained during serial passaging of clonal phenotypically heterogeneous normal cellular populations; neoplastic cellular populations; metastatic clonal cellular populations and in individual tumor transplants, grown from the original metastatic tumor. In one case, a mammary tumor arising from a single cell, within a clonal hyperplastic outgrowth, contained only mtDNA copies, harboring a deleterious “de novo” SNP variant, suggesting that only one mtDNA template may act as a template for all mtDNA copies regardless of cell phenotype. This process has been attributed to “heteroplasmic-shifting”. A process that is thought to result from selective pressure and may be responsible for pathogenic mutated mtDNA copies becoming homogeneous in clonal dominant oncogenic tissues.


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