A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer
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 glycosylaseprevents
8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic
MUTYHmutations impair this enzymatic function and are associated with colorectal cancer (CRC) in
MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-
exome sequencingthat reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC
stem cell linesor 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
MUTYHmutational 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.
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