A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer
Open accessAbstract
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.
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In COAD and PAAD, SBS18 was strongly associated with G12C mutations.
“in COAD and PAAD, SBS18 (navy blue bars), likely caused by damage from reactive oxygen species29,30, was strongly associated with G12C mutations”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [29]
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References 48 · Cited by 217
- Authors
- Viel, A., Bruselles, A., Meccia, E., Fornasarig, M., Quaia, M., Canzonieri, V., Policicchio, E., Urso, E. D., Agostini, M., Genuardi, M., Lucci-Cordisco, E., Venesio, T., Martayan, A., Diodoro, M. G., Sanchez-Mete, L., Stigliano, V., Mazzei, F., Grasso, F., Giuliani, A., Baiocchi, M., Maestro, R., Giannini, G., Tartaglia, M., Alexandrov, L. B., & Bignami, M.
- Affiliations
- Centro di Riferimento Oncologico (IT)
- Istituto Superiore di Sanità (IT)
- Bambino Gesù Children's Hospital (IT)
- University of Padua (IT)
- Agostino Gemelli University Polyclinic (IT)
- Candiolo Cancer Institute (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
- Sapienza University of Rome (IT)
- Los Alamos National Laboratory (US)
- Corresponding author
- Bignami, Margherita
- ORCID
- Viel, Alessandra
- Bruselles, Alessandro
- Meccia, Ettore
- Fornasarig, Mara
- Quaia, Michele
- Canzonieri, Vincenzo
- Urso, Emanuele Damiano
- Agostini, Marco
- Genuardi, Maurizio
- Venesio, Tiziana
- Martayan, Aline
- Diodoro, Maria Grazia
- Sanchez-Mete, Lupe
- Giuliani, Alessandro
- Baiocchi, Marta
- Maestro, Roberta
- Giannini, Giuseppe
- Tartaglia, Marco
- Alexandrov, Ludmil B.
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 20
- Pages
- 39-49
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC5478212
- OpenAlex
- W2606616407
- Cited by
- 217
- References
- 48
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 16 · 2023: 29 · 2022: 19 · 2021: 38 · 2020: 28 · 2019: 27 · 2018: 12 · 2017: 6
- FWCI
- 15.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by-nc-nd)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by-nc-nd)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- Associazione Italiana Ricerca sul Cancro (11755, 17583, 9979)
- Italian Ministry of Health (RF-2008)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- MUTYH, 8-oxoguanine, mutational signatures, colorectal cancer, MUTYH-associated polyposis, DNA glycosylase, mutator phenotype, cancer susceptibility genes, DNA mismatch repair
- MeSH terms
- Exome Sequencing, Alleles, DNA Damage, DNA Mutational Analysis, DNA Repair, Gene Frequency, Guanine, Humans, Mutation, Oncogenes, Colorectal Neoplasms, Genes, Tumor Suppressor, Genetic Predisposition to Disease, DNA Glycosylases, Microsatellite Instability, Genetic Association Studies, Mutation Rate
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