title: Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis.
abstract: 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.
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.|Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Furlan
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Trapani
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Berrino
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Debernardi
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Panero
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Libera
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.
authors.forename: Nora
authors.initials: N
authors.lastname: Sahnane
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.|Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Riva
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tibiletti
authors.affiliation: Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.|Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Venesio
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D004249:DNA Damage / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D018384:Oxidative Stress / Q000235:genetics*; D011379:Prognosis