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Cancer Genes and Genomics

Nucleotide Sequence Variation Is Frequent in the Mitochondrial DNA Displacement Loop Region of Individual Human Tumor Cells

Departments of ¹ Gene Research and ² Pathology, The Cancer Institute, and ³ Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, and ⁴ Department of Biology, Ochanomizu University, Tokyo, Japan

Requests for reprints: Katsuro Koike, Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Phone: 81-3-5791-6410; Fax: 81-3-5791-6411. E-mail: kkoike{at}jfcr.or.jp

The mitochondrial DNA (mtDNA) displacement loop (D-loop) regions of 76 various tumor cell lines were examined to investigate the existence of a specific relationship between a somatic mtDNA sequence and initiation and/or progression of a tumor. Based on molecular cloning-sequencing analysis, a nucleotide sequence in the D-loop region in each cell line was found to be homoplasmic. Several site-specific nucleotide variations were found in stomach and liver tumor cell lines more frequently than those in other tumor cell lines. Subsequently, 20 pairs of noncancerous and cancerous parts from stomach and liver tumor tissues were examined. In the liver tumor tissue, 80% of the noncancerous parts exhibited slightly higher heterogeneity than the corresponding cancerous parts. Several site-specific nucleotide variations found in 76 tumor cell lines were also detected in noncancerous or cancerous parts of stomach and liver tumor tissues. However, it remains unclear why the mtDNA D-loop sequence is homoplasmic in each tumor cell line. The data indicate that mtDNA exhibits heterogeneity even in the noncancerous part and a slight decrease in heterogeneity during tumorigenesis and/or tumor progression. Homoplasmy of the mtDNA population in the tumor cell line would be acquired in the cloning process of establishing a cell line. Site-specific nucleotide substitutions might not be directly involved in the tumorigenesis process.

Key Words: human tumor • mtDNA D-loop • nucleotide sequence variation • homoplasmy • heteroplasmy