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Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division [M. S-C., P. P., S. N., D. C., Y. X., C. J., W. M. K., D. S.], Oncology Center [M. E.], Pathology Department [T. N.], and Urology Department [M. S], Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196; University of California, San Francisco, San Francisco, California 94143-0424, Molecular Medicine and Biotechnology [R. C. K. J.]; Universitèa Campus Bio-Medico, Rome 00155, Italy; and IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Foggia 71013 Italy [P. M., V. M. F.]
Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.
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