Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer

Mitochondrial DNA (mtDNA) mutations occur in a variety of human cancers, suggesting a possible role for mitochondrial respiratory functions in tumorigenesis. Recent studies have demonstrated that SDHD, a nuclear gene encoding one of the mitochondrial complex II subunits, acts as a tumor-suppressor for hereditary paragangliomas and pheochromocytomas. In order to determine whether the SDHD function plays a wider role in human malignancies, we examined SDHD gene alterations in 52 colorectal and 59 gastric cancers and 7 cancer cell lines. Loss of heterozygosity (LOH) at the SDHD gene locus was found in 5 of 35 (14%) colorectal and 5 of 40 (13%) gastric cancers. Reduced SDHD gene expression, which was partly associated with SDHD gene LOH, was observed in 15 of 19 (79%) colorectal cancers examined. Unlike classical tumor-suppressor genes, however, partial loss rather than complete loss of the SDHD gene expression was preferentially observed and the reduced expression could not result from CpG-island methylation or coding mutation. Interestingly, the mtDNA mutations (12 cases) and the SDHD gene LOH (6 of 7 cases) did not occur in the same cancers, suggesting that these alterations might have similar functional effects in tumorigenesis. We suggest that SDHD alterations can affect mitochondrial respiratory chain functions and play a role in colorectal and gastric cancers as a distinct type of tumor suppressor.