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  • Title: Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes.
    Author: Venesio T, Balsamo A, Errichiello E, Ranzani GN, Risio M.
    Journal: Mod Pathol; 2013 Oct; 26(10):1371-81. PubMed ID: 23599153.
    Abstract:
    MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYH-associated-polyposis adenomas exhibited only c.34G>T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (P<0.001). Mutated MUTYH-associated-polyposis carcinomas showed KRAS c.34G>T transversions, prevalently occurring with BRAFV600E; none of the classical/attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P=0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P=0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation.
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