TY - JOUR
T1 - Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis
AU - Furlan, Daniela
AU - Trapani, Davide
AU - Berrino, Enrico
AU - Debernardi, Carla
AU - Panero, Mara
AU - Libera, Laura
AU - Sahnane, Nora
AU - Riva, Cristina
AU - Tibiletti, Maria Grazia
AU - Sessa, Fausto
AU - Sapino, Anna
AU - Venesio, Tiziana
PY - 2017/3/14
Y1 - 2017/3/14
N2 - 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.
AB - 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.
KW - BER
KW - colorectal adenomas
KW - DNA hypomethylation
KW - LINE-1/LINE-1 MET methylation
KW - MUTYH-associated polyposis
KW - oxidative DNA damage
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U2 - 10.1038/bjc.2017.9
DO - 10.1038/bjc.2017.9
M3 - Article
C2 - 28141798
AN - SCOPUS:85011263027
VL - 116
SP - 793
EP - 801
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 6
ER -