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A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

Journal Article · · EBioMedicine
 [1];  [2];  [3];  [4];  [1];  [4];  [5];  [6];  [7];  [8];  [8];  [9];  [10];  [10];  [10];  [10];  [3];  [3];  [3];  [2] more »;  [1];  [11];  [5];  [12];  [3] « less
  1. Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, Aviano (Italy)
  2. Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome (Italy)
  3. Istituto Superiore di Sanita, Rome (Italy)
  4. CRO Aviano National Cancer Institute, Aviano (Italy)
  5. Ospedale Pediatrico Bambino Gesu, Rome (Italy)
  6. University of Padua (Italy)
  7. University of Padua (Italy); Nano Insperid Biomedicine Lab, Istituto di Ricerca Pediatrica (IRP), Padua (Italy)
  8. Institute of Genomic Medicine, Catholic University, Rome (Italy)
  9. Unit of Pathology, Candiolo Cancer Institute-FPO (Italy)
  10. Regina Elena National Cancer Institute, Rome (Italy)
  11. University La Sapienza, Rome (Italy)
  12. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); University of New Mexico Comprehensive Cancer Center, Albuquerque, NM (United States)
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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 in this paper, 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. In conclusion, 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.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA)
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1356131
Report Number(s):
LA-UR--16-22282
Journal Information:
EBioMedicine, Journal Name: EBioMedicine Vol. 20; ISSN 2352-3964
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (48)

Bad luck and cancer: Does evolution spin the wheel of fortune? journal March 2015
MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay journal February 2010
Adenoma development in familial adenomatous polyposis and MUTYH -associated polyposis: somatic landscape and driver genes : Adenoma development in FAP and journal November 2015
Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers journal September 2012
Deciphering Signatures of Mutational Processes Operative in Human Cancer journal January 2013
2-Hydroxy-2‘-deoxyadenosine 5‘-Triphosphate Enhances A·T → C·G Mutations Caused by 8-Hydroxy-2‘-deoxyguanosine 5‘-Triphosphate by Suppressing Its Degradation upon Replication in a HeLa Extract journal May 2007
Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study journal November 2016
Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes journal April 2013
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas journal December 2012
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets journal March 2015
A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer journal May 2015
Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors journal January 2002
Mechanisms underlying mutational signatures in human cancers journal July 2014
Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability journal October 2012
Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas journal March 2004
8-oxoguanine causes spontaneous de novo germline mutations in mice journal April 2014
Landscape of Genetic Aberrations Detected in Human Colorectal Cancers journal September 2013
Multiple Colorectal Adenomas — Is Their Number Up? journal February 2003
Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase journal September 2001
Hydrolytic elimination of a mutagenic nucleotide, 8-oxodGTP, by human 18-kilodalton protein: sanitization of nucleotide pool. journal November 1992
Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage journal November 1999
Mutator Phenotype of MUTYH-null Mouse Embryonic Stem Cells journal October 2003
Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C->T:A mutations journal November 2002
Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability journal February 2004
Survival of MUTYH-Associated Polyposis Patients With Colorectal Cancer and Matched Control Colorectal Cancer Patients journal November 2010
Understanding the role of the Q338H MUTYH variant in oxidative damage repair journal March 2013
Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria journal March 2015
Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer journal June 2015
MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA journal January 2013
Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance: Colorectal Cancer Stem Cell Characterization journal March 2016
Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging journal March 2001
Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis journal June 2010
Role of MUTYH in human cancer journal March 2013
Theoretical Studies of GG-Specific Photocleavage of DNA via Electron Transfer:  Significant Lowering of Ionization Potential and 5‘-Localization of HOMO of Stacked GG Bases in B-Form DNA journal January 1996
MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events journal January 2013
Comprehensive molecular characterization of human colon and rectal cancer journal July 2012
Signatures of mutational processes in human cancer journal August 2013
Clock-like mutational processes in human somatic cells journal November 2015
Milestones of Lynch syndrome: 1895–2015 journal February 2015
Drugging the undruggable RAS: Mission Possible? journal October 2014
Multiple Colorectal Adenomas, Classic Adenomatous Polyposis, and Germ-Line Mutations in MYH journal February 2003
Only three driver gene mutations are required for the development of lung and colorectal cancers journal December 2014
Mutator Phenotype of MUTYH-null Mouse Embryonic Stem Cells journal October 2003
Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis journal April 2007
Variation in cancer risk among tissues can be explained by the number of stem cell divisions journal January 2015
High burden and pervasive positive selection of somatic mutations in normal human skin journal May 2015
Understanding the origins of human cancer journal December 2015
Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer journal June 2015

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Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis journal March 2019
Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency journal January 2020
The repertoire of mutational signatures in human cancer journal February 2020
The landscape of somatic mutation in normal colorectal epithelial cells posted_content September 2018
Evolving neoantigen profiles in colorectal cancers with DNA repair defects posted_content June 2019
Early divergence of mutational processes in human fetal tissues journal May 2019
DNA Repair Footprint Uncovers Contribution of DNA Repair Mechanism to Mutational Signatures conference November 2019
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Machine Learning Techniques for Classifying the Mutagenic Origins of Point Mutations journal May 2020
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Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies journal November 2020
Application of the adverse outcome pathway framework to genotoxic modes of action journal October 2019
NTHL1 and MUTYH polyposis syndromes: two sides of the same coin?: Base excision repair polyposis syndromes journal December 2017
Efficacy of immune checkpoint blockade in MUTYH-associated hereditary colorectal cancer journal August 2019
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Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice journal January 2020
The landscape of somatic mutation in normal colorectal epithelial cells journal October 2019
Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes journal April 2020
The missing heritability of familial colorectal cancer journal October 2019
Machine learning techniques for classifying the mutagenic origins of point mutations posted_content October 2019
SigLASSO: a LASSO approach jointly optimizing sampling likelihood and cancer mutation signatures posted_content May 2018
Hidden Markov Models Lead to Higher Resolution Maps of Mutation Signature Activity in Cancer posted_content August 2018
Molecular features of premenopausal breast cancers in Latin American women: pilot results from the PRECAMA study posted_content August 2018
Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer posted_content May 2019
Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis journal March 2019
Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis journal December 2017
Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer journal September 2017
Portrait of a cancer: mutational signature analyses for cancer diagnostics journal May 2019
Tumor sequencing is useful to refine the analysis of germline variants in unexplained high-risk breast cancer families journal April 2020
Evolving neoantigen profiles in colorectal cancers with DNA repair defects journal June 2019
Hidden Markov models lead to higher resolution maps of mutation signature activity in cancer journal July 2019
Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. text January 2017
The landscape of somatic mutation in normal colorectal epithelial cells. text January 2019
The repertoire of mutational signatures in human cancer text January 2020
Reading and Misreading 8-oxoguanine, a Paradigmatic Ambiguous Nucleobase journal May 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
8-Oxoguanine
Base excision repair
Colorectal cancer
Exome sequencing
MUTYH-associated polyposis
Mutational signature