8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-relatedmutations might contribute to the development of cancer in other organs. (C) 2017 The Authors. Published by Elsevier B.V.

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer / Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore; Fornasarig, Mara; Quaia, Michele; Canzonieri, Vincenzo; Policicchio, Eleonora; Urso, Emanuele Damiano; Agostini, Marco; Genuardi, Maurizio; Lucci-Cordisco, Emanuela; Venesio, Tiziana; Martayan, Aline; Diodoro, Maria Grazia; Sanchez-Mete, Lupe; Stigliano, Vittoria; Mazzei, Filomena; Grasso, Francesca; Giuliani, Alessandro; Baiocchi, Marta; Maestro, Roberta; Giannini, Giuseppe; Tartaglia, Marco; Alexandrov, Ludmil B.; Bignami, Margherita. - In: EBIOMEDICINE. - ISSN 2352-3964. - ELETTRONICO. - 20:(2017), pp. 39-49. [10.1016/j.ebiom.2017.04.022]

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

Canzonieri, Vincenzo;Policicchio, Eleonora;Baiocchi, Marta;Giannini, Giuseppe;
2017

Abstract

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-relatedmutations might contribute to the development of cancer in other organs. (C) 2017 The Authors. Published by Elsevier B.V.
2017
8-Oxoguanine; Base excision repair; Colorectal cancer; Exome sequencing; Mutational signature; MUTYH-associated polyposis; Biochemistry, Genetics and Molecular Biology (all)
01 Pubblicazione su rivista::01a Articolo in rivista
A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer / Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore; Fornasarig, Mara; Quaia, Michele; Canzonieri, Vincenzo; Policicchio, Eleonora; Urso, Emanuele Damiano; Agostini, Marco; Genuardi, Maurizio; Lucci-Cordisco, Emanuela; Venesio, Tiziana; Martayan, Aline; Diodoro, Maria Grazia; Sanchez-Mete, Lupe; Stigliano, Vittoria; Mazzei, Filomena; Grasso, Francesca; Giuliani, Alessandro; Baiocchi, Marta; Maestro, Roberta; Giannini, Giuseppe; Tartaglia, Marco; Alexandrov, Ludmil B.; Bignami, Margherita. - In: EBIOMEDICINE. - ISSN 2352-3964. - ELETTRONICO. - 20:(2017), pp. 39-49. [10.1016/j.ebiom.2017.04.022]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1027697
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