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Cancer Cell. 2019 Feb 11;35(2):256-266.e5. doi: 10.1016/j.ccell.2018.12.011.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.

Author information

1
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
2
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: richarda.devoer@radboudumc.nl.
3
Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
4
Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
5
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
6
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
7
Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
8
Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
9
Department of Human Genetics, University of Würzburg, 97074 Würzburg, Germany.
10
Vorarlberg Cancer Registry, Agency for Preventive and Social Medicine, Bregenz 6900, Austria.
11
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
12
Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany; Department of Internal Medicine I, University of Bonn, 53127 Bonn, Germany.
13
Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbournem, VIC 3000, Australia.
14
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia.
15
Center for Biomolecular Pharmaceutical Analyzes, UKIM Faculty of Pharmacy, 1000 Skopje, Republic of Macedonia.
16
Leeds Genetics Laboratory, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK.
17
East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
18
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC 3010, Australia.
19
Division of Human Genetics, Ohio State University Medical Centre, Columbus, OH 43221, USA.
20
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Barcelona 08908, Spain.
21
Department of Medical Genetics, St Olavs University Hospital, 7030 Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
22
Western Norway Familial Cancer Center, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
23
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
24
Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
25
Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Galicia 15706, Spain.
26
Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland.
27
Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada.
28
Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
29
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Oxford National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
30
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC 3010, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC 3010, Australia.
31
Yorkshire Regional Genetics Service and University of Leeds, Leeds LS7 4SA, UK.
32
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584 CT Utrecht, The Netherlands. Electronic address: r.kuiper@prinsesmaximacentrum.nl.

Abstract

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

KEYWORDS:

DNA repair defect; NTHL1; adenomatous polyposis; base excision repair; breast cancer; colorectal cancer; genetic predisposition; multiple malignancies; mutational signature; somatic mutation spectrum

PMID:
30753826
DOI:
10.1016/j.ccell.2018.12.011
[Indexed for MEDLINE]

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