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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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  • Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signaturemore » also presenting germline MUTYH mutations. Altogether, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types.« less
  • Among the four DNA bases, guanine is particularly vulnerable to oxidative damage and the most common oxidative product, 7,8-dihydro-8-oxoguanine (8-oxoG), is the most prevalent lesion observed in DNA molecules. Fortunately, 8-oxoG is recognized and excised by the 8-oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Ogg enzymes are divided into three separate families, namely, Ogg1, Ogg2, and archaeal GO glycosylase (AGOG). To date, structures of members of both Ogg1 and AGOG families are known but no structural information is available for members of Ogg2. Here we describe the first crystal structures of two archaeal Ogg2: Methanocaldococcus janischii Oggmore » and Sulfolobus solfataricus Ogg. A structural comparison with OGG1 and AGOG suggested that the C-terminal lysine of Ogg2 may play a key role in discriminating between guanine and 8-oxoG. This prediction was substantiated by measuring the glycosylase/lyase activity of a C-terminal deletion mutant of MjaOgg.« less
  • DNA is subject to a multitude of oxidative damages generated by oxidizing agents from metabolism and exogenous sources and by ionizing radiation. Guanine is particularly vulnerable to oxidation, and the most common oxidative product 8-oxoguanine (8-oxoG) is the most prevalent lesion observed in DNA molecules. 8-OxoG can form a normal Watson-Crick pair with cytosine (8-oxoG:C), but it can also form a stable Hoogsteen pair with adenine (8-oxoG:A), leading to a G:C {yields} T:A transversion after replication. Fortunately, 8-oxoG is recognized and excised by either of two DNA glycosylases of the base excision repair pathway: formamidopyrimidine-DNA glycosylase and 8-oxoguanine DNA glycosylasemore » (Ogg). While Clostridium acetobutylicum Ogg (CacOgg) DNA glycosylase can specifically recognize and remove 8-oxoG, it displays little preference for the base opposite the lesion, which is unusual for a member of the Ogg1 family. This work describes the crystal structures of CacOgg in its apo form and in complex with 8-oxo-2'-deoxyguanosine. A structural comparison between the apo form and the liganded form of the enzyme reveals a structural reorganization of the C-terminal domain upon binding of 8-oxoG, similar to that reported for human OGG1. A structural comparison of CacOgg with human OGG1, in complex with 8-oxoG containing DNA, provides a structural rationale for the lack of opposite base specificity displayed by CacOgg.« less