EBioMedicine (Jun 2017)
A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer
- Alessandra Viel,
- Alessandro Bruselles,
- Ettore Meccia,
- Mara Fornasarig,
- Michele Quaia,
- Vincenzo Canzonieri,
- Eleonora Policicchio,
- Emanuele Damiano Urso,
- Marco Agostini,
- Maurizio Genuardi,
- Emanuela Lucci-Cordisco,
- Tiziana Venesio,
- Aline Martayan,
- Maria Grazia Diodoro,
- Lupe Sanchez-Mete,
- Vittoria Stigliano,
- Filomena Mazzei,
- Francesca Grasso,
- Alessandro Giuliani,
- Marta Baiocchi,
- Roberta Maestro,
- Giuseppe Giannini,
- Marco Tartaglia,
- Ludmil B. Alexandrov,
- Margherita Bignami
Affiliations
- Alessandra Viel
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, Aviano, Italy
- Alessandro Bruselles
- Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Ettore Meccia
- Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
- Mara Fornasarig
- Unit of Gastroenterology, CRO Aviano National Cancer Institute, Aviano, Italy
- Michele Quaia
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, Aviano, Italy
- Vincenzo Canzonieri
- Unit of Pathology, CRO Aviano National Cancer Institute, Aviano, Italy
- Eleonora Policicchio
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- Emanuele Damiano Urso
- First Surgical Clinic, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
- Marco Agostini
- First Surgical Clinic, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
- Maurizio Genuardi
- Institute of Genomic Medicine, Catholic University, Rome, Italy
- Emanuela Lucci-Cordisco
- Institute of Genomic Medicine, Catholic University, Rome, Italy
- Tiziana Venesio
- Unit of Pathology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy
- Aline Martayan
- Division of Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, Rome, Italy
- Maria Grazia Diodoro
- Division of Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, Rome, Italy
- Lupe Sanchez-Mete
- Division of Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, Rome, Italy
- Vittoria Stigliano
- Division of Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, Rome, Italy
- Filomena Mazzei
- Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
- Francesca Grasso
- Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
- Alessandro Giuliani
- Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
- Marta Baiocchi
- Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Roberta Maestro
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, Aviano, Italy
- Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
- Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- Ludmil B. Alexandrov
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
- Margherita Bignami
- Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
- DOI
- https://doi.org/10.1016/j.ebiom.2017.04.022
- Journal volume & issue
-
Vol. 20,
no. C
pp. 39 – 49
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-related mutations might contribute to the development of cancer in other organs.
Keywords
- MUTYH-associated polyposis
- Colorectal cancer
- 8-Oxoguanine
- Base excision repair
- Exome sequencing
- Mutational signature
