Multicenter Study

. 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

Judith E Grolleman¹, Richarda M de Voer², Fadwa A Elsayed³, Maartje Nielsen⁴, Robbert D A Weren¹, Claire Palles⁵, Marjolijn J L Ligtenberg⁶, Janet R Vos⁷, Sanne W Ten Broeke⁴, Noel F C C de Miranda³, Renske A Kuiper¹, Eveline J Kamping¹, Erik A M Jansen¹, M Elisa Vink-Börger⁸, Isabell Popp⁹, Alois Lang¹⁰, Isabel Spier¹¹, Robert Hüneburg¹², Paul A James¹³, Na Li¹⁴, Marija Staninova¹⁵, Helen Lindsay¹⁶, David Cockburn¹⁶, Olivera Spasic-Boskovic¹⁷, Mark Clendenning¹⁸, Kevin Sweet¹⁹, Gabriel Capellá²⁰, Wenche Sjursen²¹, Hildegunn Høberg-Vetti²², Marjolijn C Jongmans¹, Kornelia Neveling¹, Ad Geurts van Kessel¹, Hans Morreau³, Frederik J Hes⁴, Rolf H Sijmons²³, Hans K Schackert²⁴, Clara Ruiz-Ponte²⁵, Dagmara Dymerska²⁶, Jan Lubinski²⁶, Barbara Rivera²⁷, William D Foulkes²⁸, Ian P Tomlinson²⁹, Laura Valle²⁰, Daniel D Buchanan³⁰, Sue Kenwrick¹⁷, Julian Adlard³¹, Aleksandar J Dimovski¹⁵, Ian G Campbell¹⁴, Stefan Aretz¹¹, Detlev Schindler⁹, Tom van Wezel³, Nicoline Hoogerbrugge¹, Roland P Kuiper³²

Affiliations

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.

PMID: 30753826
DOI: 10.1016/j.ccell.2018.12.011

Free article

Multicenter Study

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

Judith E Grolleman et al. Cancer Cell. 2019.

Free article

. 2019 Feb 11;35(2):256-266.e5.

doi: 10.1016/j.ccell.2018.12.011.

Authors

Affiliations

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.

PMID: 30753826
DOI: 10.1016/j.ccell.2018.12.011

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.

PubMed Disclaimer

Cited by

Monoallelic NTHL1 Loss-of-Function Variants and Risk of Polyposis and Colorectal Cancer.
Elsayed FA, Grolleman JE, Ragunathan A; NTHL1 study group; Buchanan DD, van Wezel T, de Voer RM. Elsayed FA, et al. Gastroenterology. 2020 Dec;159(6):2241-2243.e6. doi: 10.1053/j.gastro.2020.08.042. Epub 2020 Aug 26. Gastroenterology. 2020. PMID: 32860789 Free PMC article. No abstract available.
A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis.
Altaraihi M, Gerdes AM, Wadt K. Altaraihi M, et al. Hum Genome Var. 2019 Oct 10;6:46. doi: 10.1038/s41439-019-0077-3. eCollection 2019. Hum Genome Var. 2019. PMID: 31645984 Free PMC article.
The impact of rare germline variants on human somatic mutation processes.
Vali-Pour M, Park S, Espinosa-Carrasco J, Ortiz-Martínez D, Lehner B, Supek F. Vali-Pour M, et al. Nat Commun. 2022 Jun 28;13(1):3724. doi: 10.1038/s41467-022-31483-1. Nat Commun. 2022. PMID: 35764656 Free PMC article.
NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas.
Belhadj S, Quintana I, Mur P, Munoz-Torres PM, Alonso MH, Navarro M, Terradas M, Piñol V, Brunet J, Moreno V, Lázaro C, Capellá G, Valle L. Belhadj S, et al. Sci Rep. 2019 Jun 21;9(1):9020. doi: 10.1038/s41598-019-45281-1. Sci Rep. 2019. PMID: 31227763 Free PMC article.
Genetics, diet, microbiota, and metabolome: partners in crime for colon carcinogenesis.
La Vecchia M, Sala G, Sculco M, Aspesi A, Dianzani I. La Vecchia M, et al. Clin Exp Med. 2024 Oct 29;24(1):248. doi: 10.1007/s10238-024-01505-x. Clin Exp Med. 2024. PMID: 39470880 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

Grants and funding

16459/CRUK_/Cancer Research UK/United Kingdom

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- The Lens - Patent Citations Database

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources