Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma

Shuji Nomoto, Katsuya Yamashita, Katsumi Koshikawa, Akimasa Nakao, David Sidransky

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


Purpose: Hepatocellular carcinoma (HCC) is a highly malignant tumor prone to multicentric occurrence. Differentiation between a true relapse of HCC and a second primary tumor is of clinical importance. We sought to identify mitochondrial mutations in HCC and test their use as clonal markers in this disease. Experimental Design: Primary HCC tissue samples were obtained from 19 patients and analyzed for mutations within the mitochondrial displacement loop (D-loop). The discovered mutations were used to determine tumor clonality and provided the basis for detection of tumor DNA in corresponding plasma samples. Results: Thirteen of 19 HCC cases (68%) were identified as having D-loop mitochondrial DNA (mtDNA) mutations in at least one tumor. In 3 of these 13 cases, the same mutation was observed in multiple tumors, indicating monoclonal origin. Remarkably, in 8 of 13 mutated cases, we detected deletion/insertion mutations in the C-tract, a recently reported hotspot and potential replication start site of the closed, circular mitochondrial genome. In addition, we detected mutant mtDNA in 8 of 10 tested paired plasma DNA samples using a highly sensitivity molecular assay. Conclusions: mtDNA mutations within the D-loop control region are a frequent event in HCC, providing a molecular tool for the determination of clonality. In addition, detection of tumor-specific mtDNA mutations in plasma DNA needs to be explored further for monitoring patients with primary HCC.

Original languageEnglish (US)
Pages (from-to)481-487
Number of pages7
JournalClinical Cancer Research
Issue number2
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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