Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck

doi:10.1073/pnas.0610818104

Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck

*Department of Otolaryngology–Head and Neck Surgery,
^†Department of Oncology,
^‖Department of Surgery, Division of Plastic and Reconstructive Surgery,
**Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287;
^¶Jefferson Medical College, Philadelphia, PA 19107;
^††Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and
^§Laboratory of Molecular Medicine and Biotechnology, University Campus BioMedico School of Medicine, 00155 Rome, Italy

Edited by Harold E. Varmus, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved March 13, 2007 (received for review December 6, 2006)

Abstract

Mitochondrial genomic mutations are found in a variety of human cancers; however, the frequency of mitochondrial DNA (mtDNA) mutations in coding regions remains poorly defined, and the functional effects of mitochondrial mutations found in primary human cancers are not well described. Using MitoChip, we sequenced the whole mitochondrial genome in 83 head and neck squamous cell carcinomas. Forty-one of 83 (49%) tumors contained mtDNA mutations. Mutations occurred within noncoding (D-loop) and coding regions. A nonrandom distribution of mutations was found throughout the mitochondrial enzyme complex components. Sequencing of margins with dysplasia demonstrated an identical nonconservative mitochondrial mutation (A76T in ND4L) as the tumor, suggesting a role of mtDNA mutation in tumor progression. Analysis of p53 status showed that mtDNA mutations correlated positively with p53 mutations (P < 0.002). To characterize biological function of the mtDNA mutations, we cloned NADH dehydrogenase subunit 2 (ND2) mutants based on primary tumor mutations. Expression of the nuclear-transcribed, mitochondrial-targeted ND2 mutants resulted in increased anchorage-dependent and -independent growth, which was accompanied by increased reactive oxygen species production and an aerobic glycolytic metabolic phenotype with hypoxia-inducible factor (HIF)-1α induction that is reversible by ascorbate. Cancer-specific mitochondrial mutations may contribute to development of a malignant phenotype by direct genotoxic effects from increased reactive oxygen species production as well as induction of aerobic glycolysis and growth promotion.

Footnotes

^‡‡To whom correspondence should be addressed at:
Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins Medical Institutions, 601 North Caroline Street, 6th Floor, Baltimore, MD 21287-0910.
E-mail: jcalifa{at}jhmi.edu
Author contributions: J.A.C. designed research; S.Z., S.K., W.S., G.W., A. Chuang, L.P., L.G., S.K.M., A. Chatterjee, W.H.W., C.G., M.C., T.M., and A.V. performed research; S.Z., W.K., A.M., and D.S. analyzed data; and S.Z. and J.A.C. wrote the paper.
↵ ^‡Present address: Karmanos Cancer Institute, Department of Pathology, Wayne State University, 4100 John R Street, Detroit, MI 48201.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0610818104/DC1.
Abbreviations:

ND2,

NADH dehydrogenase subunit 2;

HIF,

hypoxia-inducible factor;

ROS,

reactive oxygen species.