Mitochondrial D310 mutations in colorectal adenomas: an early but not causative genetic event during colorectal carcinogenesis

Somatic mutations of the D310 sequence of the mitochondrial DNA are reported in human cancers, including colorectal cancers (CRC). The presence of these mutations at early or late steps of colorectal carcinogenesis is unknown. Their prevalence increased significantly with the number of cytosines in the D310 sequence of the matched normal tissue (D310 polymorphism), suggesting that this polymorphism could be a risk factor for CRC. The aim of this study was (i) to investigate the prevalence of D310 mutations in 64 colorectal adenomas and 36 liver metastases from 15 CRC patients, (ii) to assess the relation between D310 polymorphism and the risk of colorectal adenoma in a case-control study including 613 cases with colorectal adenoma and 572 polyp-free (PF) controls. D310 mutations were found in colorectal adenomas and liver metastases from CRC patients in 27 and 33%, respectively and so are an early genetic event in colorectal carcinogenesis. The frequency of the mutations increased significantly with the number of cytosines in the matched normal tissue D310 sequence (p < 0.001) but the distribution of D310 polymorphisms was not significantly different between adenoma cases (large (>9 mm) and small (<5 mm) adenomas) and PF controls (C(4)-C(7)TC(6): 47, 52 and 49%; C(8)TC(6): 44, 39 and 41%; C(9)-C(10)TC(6): 9, 9 and 10%, respectively; p > 0.05), suggesting that germline D310 polymorphism is not a risk factor for colorectal adenomas. Considering their high frequency in colorectal adenomas, mitochondrial D310 mutations could represent a biomarker for early detection of CRC although their causative role in colorectal carcinogenesis remains uncertain.