A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer
Autor: | Eleonora Policicchio, Filomena Mazzei, Alessandro Bruselles, Marco Tartaglia, Mara Fornasarig, Alessandra Viel, Roberta Maestro, Maurizio Genuardi, Ettore Meccia, Francesca Grasso, Vittoria Stigliano, Marco Agostini, Marta Baiocchi, Michele Quaia, Giuseppe Giannini, Aline Martayan, Emanuela Lucci-Cordisco, Emanuele Damiano Luca Urso, Vincenzo Canzonieri, Lupe Sanchez-Mete, Maria Grazia Diodoro, Margherita Bignami, Ludmil B. Alexandrov, Alessandro Giuliani, Tiziana Venesio |
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Přispěvatelé: | 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 |
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Exome sequencing DNA Repair DNA Mutational Analysis 8-Oxoguanine lcsh:Medicine medicine.disease_cause Whole Exome Sequencing MUTYH-associated polyposis Colorectal cancer Base excision repair Mutational signature DNA Glycosylases chemistry.chemical_compound Gene Frequency Mutation Rate Genes Tumor Suppressor Biochemistry Genetics and Molecular Biology (all) Genetics Mutation lcsh:R5-920 MUTYH-Associated Polyposis General Medicine Microsatellite Instability Colorectal Neoplasms lcsh:Medicine (General) Tumor Suppressor Research Paper Guanine DNA repair DNA damage Alleles Genetic Association Studies Genetic Predisposition to Disease Humans Oncogenes DNA Damage Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences MUTYH medicine neoplasms MUTYH-associated polyposi Settore MED/06 - ONCOLOGIA MEDICA lcsh:R digestive system diseases 030104 developmental biology chemistry Genes |
Zdroj: | EBioMedicine, Vol 20, Iss C, Pp 39-49 (2017) EBioMedicine |
ISSN: | 2352-3964 |
Popis: | 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-related mutations might contribute to the development of cancer in other organs. Graphical Abstract Image 1 Highlights • A modest mutator phenotype in MUTYH-defective colorectal cancer • Novel mutational signature of G>T mutations from persisting 8-oxoguanine:A mispair • This mutational signature is present in oncogenes/tumor suppressor associated with colorectal cancer • The mutational signature allows identifying a role for 8-oxoguanine-related mutations in other types of human cancer. Viel et al. identifies by exome-sequencing a mutational signature in colorectal cancer defective in the MUTYH DNA glycosylase, a DNA repair gene preventing 8-oxoguanine-related mutagenesis. A strong sequence dependence of G > T transversions characterizes this mutational fingerprint and unveils the contribution of persistent 8-oxoG:A mismatches in human cancer. |
Databáze: | OpenAIRE |
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