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, Alessandro Giuliani, Francesca Grasso, Marta BaiocchiRoberta Maestro, Giuseppe Giannini, Marco Tartaglia, Ludmil B Alexandrov, Margherita Bignami

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)39-49
Number of pages11
JournalEBioMedicine
Volume20
DOIs
Publication statusPublished - Jun 2017

Fingerprint

Colorectal Neoplasms
Adenine
Mutation
DNA
DNA Glycosylases
Exome
Neoplasms
Mutagenesis
Neoplastic Stem Cells
Stem cells
DNA Replication
Tumors
Genes
Phenotype
Cell Line
8-hydroxyguanine

Keywords

  • Alleles
  • Colorectal Neoplasms/genetics
  • DNA Damage
  • DNA Glycosylases/genetics
  • DNA Mutational Analysis
  • DNA Repair
  • Gene Frequency
  • Genes, Tumor Suppressor
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Guanine/analogs & derivatives
  • Humans
  • Microsatellite Instability
  • Mutation
  • Mutation Rate
  • Oncogenes
  • Whole Exome Sequencing

Cite this

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. / 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; Giuliani, Alessandro; Grasso, Francesca; Baiocchi, Marta; Maestro, Roberta; Giannini, Giuseppe; Tartaglia, Marco; Alexandrov, Ludmil B; Bignami, Margherita.

In: EBioMedicine, Vol. 20, 06.2017, p. 39-49.

Research output: Contribution to journalArticle

Viel, A, Bruselles, A, Meccia, E, Fornasarig, M, Quaia, M, Canzonieri, V, Policicchio, E, Urso, ED, Agostini, M, Genuardi, M, Lucci-Cordisco, E, Venesio, T, Martayan, A, Diodoro, MG, Sanchez-Mete, L, Stigliano, V, Mazzei, F, Giuliani, A, Grasso, F, Baiocchi, M, Maestro, R, Giannini, G, Tartaglia, M, Alexandrov, LB & Bignami, M 2017, 'A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer', EBioMedicine, vol. 20, pp. 39-49. https://doi.org/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 ; Giuliani, Alessandro ; Grasso, Francesca ; 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. In: EBioMedicine. 2017 ; Vol. 20. pp. 39-49.
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AU - Viel, Alessandra

AU - Bruselles, Alessandro

AU - Meccia, Ettore

AU - Fornasarig, Mara

AU - Quaia, Michele

AU - Canzonieri, Vincenzo

AU - Policicchio, Eleonora

AU - Urso, Emanuele Damiano

AU - Agostini, Marco

AU - Genuardi, Maurizio

AU - Lucci-Cordisco, Emanuela

AU - Venesio, Tiziana

AU - Martayan, Aline

AU - Diodoro, Maria Grazia

AU - Sanchez-Mete, Lupe

AU - Stigliano, Vittoria

AU - Mazzei, Filomena

AU - Giuliani, Alessandro

AU - Grasso, Francesca

AU - Baiocchi, Marta

AU - Maestro, Roberta

AU - Giannini, Giuseppe

AU - Tartaglia, Marco

AU - Alexandrov, Ludmil B

AU - Bignami, Margherita

N1 - Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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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KW - Colorectal Neoplasms/genetics

KW - DNA Damage

KW - DNA Glycosylases/genetics

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Gene Frequency

KW - Genes, Tumor Suppressor

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Guanine/analogs & derivatives

KW - Humans

KW - Microsatellite Instability

KW - Mutation

KW - Mutation Rate

KW - Oncogenes

KW - Whole Exome Sequencing

U2 - 10.1016/j.ebiom.2017.04.022

DO - 10.1016/j.ebiom.2017.04.022

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C2 - 28551381

VL - 20

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EP - 49

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -