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
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
Externí odkaz: