Journal article

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Na Li, Magnus Zethoven, Simone McInerny, Lisa Devereux, Yu-Kuan Huang, Niko Thio, Dane Cheasley, Sara Gutierrez-Enriquez, Alejandro Moles-Fernandez, Orland Diez, Tu Nguyen-Dumont, Melissa C Southey, John L Hopper, Jacques Simard, Martine Dumont, Penny Soucy, Alfons Meindl, Rita Schmutzler, Marjanka K Schmidt, Muriel A Adank Show all

npj Breast Cancer | NATURE RESEARCH | Published : 2021

Abstract

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international stu..

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Grants

Awarded by National Breast Cancer Foundation


Awarded by Cancer Australia/National Breast Cancer Foundation


Awarded by National Health and Medical Research Council of Australia


Awarded by Ligue Nationale contre le Cancer


Awarded by French National Institute of Cancer (INCa)


Awarded by France Genomique National infrastructure - "Investissements d'Avenir" program


Awarded by Canadian Institutes of Health Research


Awarded by Ministere de l'Economie, de la Science et de l'Innovation du Quebec


Awarded by German Cancer Aid


Awarded by Ministry for Innovation, Science, and Research of the State of North Rhine-Westphalia


Awarded by USA National Cancer Institute


Awarded by Cancer Research UK


Awarded by European Union's Horizon 2020 Research and Innovation Program (BRIDGES)


Awarded by Spanish Instituto de Salud Carlos III (ISCIII), an initiative of the Spanish Ministry of Economy and Innovation


Awarded by ISCIII Miguel Servet Program contract


Awarded by comprehensive cancer center SiRIC (Site de Recherche Integree sur le Cancer)


Awarded by National Breast Cancer Foundation (Australia)


Funding Acknowledgements

The BEACCON study was supported by the National Breast Cancer Foundation (IF-15-004, I.G.C. and P.A.J.), Cancer Australia/National Breast Cancer Foundation (PdCCRS_1107870, I.G.C. and P.A.J.), the Victorian Cancer Agency (Tumor Stream Grant, P.A.J.) and the National Health and Medical Research Council of Australia (GNT1023698, P.A.J.; GNT1041975, I.G.C.). Na Li is supported by Cancer Council Victoria. The authors thank Simone M. Rowley, Jue Er Amand a Lee, Norah Grewal, Gisela Mir Arnau, Timothy Semple, Jason Li, Kaushalya Amarasinghe and Richard Lupat for helping with the sequencing and bioinformatic analysis. We also thank Lyon Mascarenhas, Rebecca Driessen, for the ViP study site principal investigators Geoffrey Lindeman, Marion Harris, Tom John, and Ingrid Winship, and the staff at the Victorian and Tasmanian Familial Cancer Centers who enrolled participants and provided clinical data. We also thank all the participants of the ViP and Lifepool studies for donating their DNA samples and clinical information. GENESIS (GENE SISters) is a French national study coordinated by D. Stoppa-Lyonnet and N. Andrieu and sponsored by UNICANCER (Sinilnikova et al. BMC Cancer 2016). We wish to thank the genetic epidemiology platform (the PIGE, Plateforme d'Investigation en Genetique et Epidemiologie: Severine Eon-Marchais, M. Marcou, D. Le Gal, L. Toulemonde, J. Beauvallet, N. Mebirouk, E. Cavaciuti), the biological resource center (S. Mazoyer, F. Damiola, L. Barjhoux, C. Verny-Pierre, V. Sornin) and all the GENESIS collaborating cancer clinics. Financial support for GENESIS was provided by the Ligue Nationale contre le Cancer (grants PRE05/DSL and PRE07/DSL), the French National Institute of Cancer (INCa grant No b2008-029/LL-LC) and the comprehensive cancer center SiRIC (Site de Recherche Integree sur le Cancer: Grant INCa-DGOS-4654). Exome sequencing was supported by the France Genomique National infrastructure, funded as part of the "Investissements d'Avenir" program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09) and the Centre National de Recherche en Genomique Humaine, CEA. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l'Innovation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation. The PRE<SUP>3</SUP>VENTION project was supported by a grant from the Ministere de l'Economie, de la Science et de l'Innovation du Quebec through the PSR-SIIRI-949 program. The CARTaGENE study was supported by Genome Canada. The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is funded by the German Cancer Aid (#110837, #70111850, coordinator: Rita K. Schmutzler, Cologne). Next-generation sequencing of female control individuals was supported by the Ministry for Innovation, Science, and Research of the State of North Rhine-Westphalia (#323-8.0302.16.02-132142) and LIFE not signnot sign- Leipzig Research Center for Civilization Diseases, Universitat Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by means of the Free State of Saxony within the framework of the excellence initiative. This work was also supported by grant UM1 CA164920 from the USA National Cancer Institute.The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. The sequencing and analysis for this project were funded by the European Union's Horizon 2020 Research and Innovation Program (BRIDGES: grant number 634935). The work in VHIO was supported by the Spanish Instituto de Salud Carlos III (ISCIII) funding granted to Sara Gutierrez-Enriquez (PI16/01218 and PI19/01303), an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds. Sara Gutierrez-Enriquez is recipient of an ISCIII Miguel Servet Program contract (CP16/00034). The VHIO authors acknowledge the Cellex Foundation for providing research facilities and thank CERCA Program / Generalitat de Catalunya for institutional support. Tu Nguyen-Dumont is the recipient of a Career Development Fellowship from the National Breast Cancer Foundation (ECF-17-001, Australia).