Daniela Furlan et al., Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis. British Journal of Cancer

Daniela Furlan1,2, Davide Trapani1, Enrico Berrino3, Carla Debernardi3, Mara Panero3, Laura Libera1, Nora Sahnane1, Cristina Riva1,2, Maria Grazia Tibiletti1, Fausto Sessa1,2, Anna Sapino3 and Tiziana Venesio3

1Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy
2Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy
3Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy


Background: A compromised base excision repair (BER) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis, a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine. Remarkably, DNA global demethylation has been shown to be mediated by BER, suggesting a relevant interplay with early colorectal tumourigenesis. To check this hypothesis, we investigated a cohort of 49 adenomas and 10 carcinomas, derived from 17 MUTYH-associated polyposis patients; as adenoma controls, we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps.

Methods: Samples were analysed for their mutational and epigenetic status, measured as global LINE-1 (long interspersed nuclear element) and gene-specific LINE-1 MET methylation by mass spectrometry and pyrosequencing.

Results: MUTYH-associated polyposis adenomas were strikingly more hypomethylated than familial adenomatous and sporadic polyps for both DNA demethylation markers (P=0.032 and P=0.007 for LINE-1; P=0.004 and P<0.0001 for LINE-1 MET, respectively) with levels comparable to those of the carcinomas derived from the same patients. They also had mutations due mainly to KRAS/NRAS p.G12C, which was absent in the controls (P<0.0001 for both sets).

Conclusions: Our results show that DNA demethylation, together with specific KRAS/NRAS mutations, drives the early steps of oxidative damage colorectal tumourigenesis.

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