PURPOSE: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1. EXPERIMENTAL DESIGN: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families. RESULTS: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. CONCLUSIONS: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.
PURPOSE: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1. EXPERIMENTAL DESIGN: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families. RESULTS: Eight rare variants and 5 frequent variants were found in MSS-HNPCCpatients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. CONCLUSIONS: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.
Authors: Rosa M Xicola; Sneha Bontu; Brian J Doyle; Jamie Rawson; Pilar Garre; Esther Lee; Miguel de la Hoya; Xavier Bessa; Joan Clofent; Luis Bujanda; Francesc Balaguer; Sergi Castellví-Bel; Cristina Alenda; Rodrigo Jover; Clara Ruiz-Ponte; Sapna Syngal; Montserrat Andreu; Angel Carracedo; Antoni Castells; Polly A Newcomb; Noralane Lindor; John D Potter; John A Baron; Nathan A Ellis; Trinidad Caldes; Xavier LLor Journal: Carcinogenesis Date: 2016-05-27 Impact factor: 4.944
Authors: Andrea Degasperi; Xueqing Zou; Tauanne Dias Amarante; Andrea Martinez-Martinez; Gene Ching Chiek Koh; João M L Dias; Laura Heskin; Lucia Chmelova; Giuseppe Rinaldi; Valerie Ya Wen Wang; Arjun S Nanda; Aaron Bernstein; Sophie E Momen; Jamie Young; Daniel Perez-Gil; Yasin Memari; Cherif Badja; Scott Shooter; Jan Czarnecki; Matthew A Brown; Helen R Davies; Serena Nik-Zainal Journal: Science Date: 2022-04-22 Impact factor: 63.714