TY - JOUR
T1 - A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer.
AU - Viel, Alessandra
AU - Bruselles, Alessandro
AU - Meccia, Ettore
AU - Fornasarig, Mara
AU - Quaia, Michele
AU - Canzonieri, Vincenzo
AU - Policicchio, Eleonora
AU - Urso, Emanuele Damiano
AU - Agostini, Marco
AU - Genuardi, Maurizio
AU - Lucci Cordisco, Emanuela
AU - Venesio, Tiziana
AU - Martayan, Aline
AU - Diodoro, Maria Grazia
AU - Sanchez-Mete, Lupe
AU - Stigliano, Vittoria
AU - Mazzei, Filomena
AU - Mazzei, Francesca
AU - Grasso, Francesca
AU - Giuliani, Alessandro
AU - Baiocchi, Marta
AU - Maestro, Roberta
AU - Giannini, Giuseppe
AU - Tartaglia, Marco
AU - Alexandrov, Ludmil B.
AU - Bignami, Margherita
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - 8-Oxoguanine
KW - 8-Oxoguanine
UR - http://hdl.handle.net/10807/111918
U2 - 10.1016/j.ebiom.2017.04.022
DO - 10.1016/j.ebiom.2017.04.022
M3 - Article
SN - 2352-3964
SP - 39
EP - 49
JO - EBioMedicine
JF - EBioMedicine
ER -
