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

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 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.

Authors:
 [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)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1356131
Report Number(s):
LA-UR-16-22282
Journal ID: ISSN 2352-3964
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
EBioMedicine
Additional Journal Information:
Journal Volume: 20; Journal ID: ISSN 2352-3964
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; MUTYH-associated polyposis; Colorectal cancer; 8-Oxoguanine; Base excision repair; Exome sequencing; Mutational signature

Citation Formats

Viel, Alessandra, Bruselles, Alessandro, Meccia, Ettore, Fornasarig, Mara, Quaia, Michele, Canzonieri, Vincenzo, Policicchio, Eleonora, Urso, Emanuele Damiano, Agostini, Marco, Genuardi, Maurizio, Lucci-Cordisco, Emanuela, Venesio, Tiziana, Martayan, Aline, Diodoro, Maria Grazia, Sanchez-Mete, Lupe, Stigliano, Vittoria, Mazzei, Filomena, Grasso, Francesca, Giuliani, Alessandro, Baiocchi, Marta, Maestro, Roberta, Giannini, Giuseppe, Tartaglia, Marco, Alexandrov, Ludmil B., and Bignami, Margherita. A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. United States: N. p., 2017. Web. doi:10.1016/j.ebiom.2017.04.022.
Viel, Alessandra, Bruselles, Alessandro, Meccia, Ettore, Fornasarig, Mara, Quaia, Michele, Canzonieri, Vincenzo, Policicchio, Eleonora, Urso, Emanuele Damiano, Agostini, Marco, Genuardi, Maurizio, Lucci-Cordisco, Emanuela, Venesio, Tiziana, Martayan, Aline, Diodoro, Maria Grazia, Sanchez-Mete, Lupe, Stigliano, Vittoria, Mazzei, Filomena, Grasso, Francesca, Giuliani, Alessandro, Baiocchi, Marta, Maestro, Roberta, Giannini, Giuseppe, Tartaglia, Marco, Alexandrov, Ludmil B., & Bignami, Margherita. A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. United States. doi:10.1016/j.ebiom.2017.04.022.
Viel, Alessandra, Bruselles, Alessandro, Meccia, Ettore, Fornasarig, Mara, Quaia, Michele, Canzonieri, Vincenzo, Policicchio, Eleonora, Urso, Emanuele Damiano, Agostini, Marco, Genuardi, Maurizio, Lucci-Cordisco, Emanuela, Venesio, Tiziana, Martayan, Aline, Diodoro, Maria Grazia, Sanchez-Mete, Lupe, Stigliano, Vittoria, Mazzei, Filomena, Grasso, Francesca, Giuliani, Alessandro, Baiocchi, Marta, Maestro, Roberta, Giannini, Giuseppe, Tartaglia, Marco, Alexandrov, Ludmil B., and Bignami, Margherita. Thu . "A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer". United States. doi:10.1016/j.ebiom.2017.04.022. https://www.osti.gov/servlets/purl/1356131.
@article{osti_1356131,
title = {A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer},
author = {Viel, Alessandra and Bruselles, Alessandro and Meccia, Ettore and Fornasarig, Mara and Quaia, Michele and Canzonieri, Vincenzo and Policicchio, Eleonora and Urso, Emanuele Damiano and Agostini, Marco and Genuardi, Maurizio and Lucci-Cordisco, Emanuela and Venesio, Tiziana and Martayan, Aline and Diodoro, Maria Grazia and Sanchez-Mete, Lupe and Stigliano, Vittoria and Mazzei, Filomena and Grasso, Francesca and Giuliani, Alessandro and Baiocchi, Marta and Maestro, Roberta and Giannini, Giuseppe and Tartaglia, Marco and Alexandrov, Ludmil B. and Bignami, Margherita},
abstractNote = {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.},
doi = {10.1016/j.ebiom.2017.04.022},
journal = {EBioMedicine},
number = ,
volume = 20,
place = {United States},
year = {Thu Apr 13 00:00:00 EDT 2017},
month = {Thu Apr 13 00:00:00 EDT 2017}
}

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