Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors

Montserrat Sanchez-Cespedes, Paola Parrella, Shuji Nomoto, Daniel Cohen, Yan Xiao, Carmen Jeronimo, Wayne M. Koch, David Sidransky, Manel Esteller, Theresa Nicol, Mark Schoenberg, Richard C.K. Jordan, Richard C.K. Jordan, Paola Mazzarelli, Vito M. Fazio

Research output: Contribution to journalArticlepeer-review

229 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)7015-7019
Number of pages5
JournalCancer research
Issue number19
StatePublished - Oct 1 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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