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  • Oncogenomics
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Nuclear–mitochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells

Oncogene volume 25, pages 6336–6344 (2006)Cite this article

Abstract

Analyses of genome orthologs in cancer on the background of tumor heterogeneity, coupled with the recent identification that the tumor propagating capacity resides within a very small fraction of cells (the tumor stem cells-TSCs), has not been achieved. Here, we describe a strategy to explore genetic drift in the mitochondrial genome accompanying varying stem cell dynamics in epithelial ovarian cancer. A major and novel outcome is the identification of a specific mutant mitochondrial DNA profile associated with the TSC lineage that is drastically different from the germ line profile. This profile, however, is often camouflaged in the primary tumor, and sometimes may not be detected even after metastases, questioning the validity of whole tumor profiling towards determining individual prognosis. Continuing mutagenesis in subsets with a mutant mitochondrial genome could result in transformation through a cooperative effect with nuclear genes – a representative example in our study is a tumor suppressor gene viz. cAMP responsive element binding binding protein. This specific profile could be a critical predisposing step undertaken by a normal stem cell to overcome a tightly regulated mutation rate and DNA repair in its evolution towards tumorigenesis. Our findings suggest that varying stem cell dynamics and mutagenesis define TSC progression that may clinically translate into increasing tumor aggression with serious implications for prognosis.

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Abbreviations

CREBBP :

cAMP responsive element binding binding protein

TSC:

tumor stem cells

mtDNA:

mitochondrial DNA

ROS:

reactive oxygen species

AMP:

adenosine mono-phosphate

CRS:

Cambridge Reference Sequence

NHRD:

nuclear hormone receptor domain

KIX:

CREB binding domain

HAT:

histone acetyltransferase

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Acknowledgements

We thank Dr GC Mishra, Director, National Center for Cell Science (Pune, India) for encouragement and support. This work is funded by the Department of Biotechnology (DBT). Ms N Sharma receives a research fellowship from the Council of Scientific and Industrial Research (CSIR). We also thank Dr CB Koppikar (Jehangir Hospital, Pune, India) and Dr Sanjay Gupte (Gupte Hospital, Pune) for providing the tissue and tumor samples, Mr Sarang Satoor for the backup in DNA sequencing and Mr AM Mali for excellent technical assistance. Statistical analysis was carried out under the kind guidance of Dr AP Gore (Department of Statistics, Pune University, India).

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Author notes

  1. A A Wani, N Sharma and S A Bapat: These authors contributed equally to this work.

Authors and Affiliations

  1. National Centre for Cell Science, Ganeshkhind, Pune, Maharashtra, India

    A A Wani, N Sharma, Y S Shouche & S A Bapat

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  1. A A Wani
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Correspondence to S A Bapat.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wani, A., Sharma, N., Shouche, Y. et al. Nuclear–mitochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells. Oncogene 25, 6336–6344 (2006). https://doi.org/10.1038/sj.onc.1209649

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