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Li N, Zethoven M, McInerny S, et al. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. NPJ Breast Cancer. 2021;7(1):52doi: 10.1038/s41523-021-00255-3.
Li, N., Zethoven, M., McInerny, S., Devereux, L., Huang, Y. K., Thio, N., Cheasley, D., Gutiérrez-Enríquez, S., Moles-Fernández, A., Diez, O., Nguyen-Dumont, T., Southey, M. C., Hopper, J. L., Simard, J., Dumont, M., Soucy, P., Meindl, A., Schmutzler, R., Schmidt, M. K., Adank, M. A., Andrulis, I. L., Hahnen, E., Engel, C., Lesueur, F., Girard, E., Neuhausen, S. L., Ziv, E., Allen, J., Easton, D. F., Scott, R. J., Gorringe, K. L., James, P. A., & Campbell, I. G. (2021). Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. NPJ breast cancer, 7(1), 52. https://doi.org/10.1038/s41523-021-00255-3
Li, Na, et al. "Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects." NPJ breast cancer vol. 7,1 (2021): 52. doi: https://doi.org/10.1038/s41523-021-00255-3
Li N, Zethoven M, McInerny S, Devereux L, Huang YK, Thio N, Cheasley D, Gutiérrez-Enríquez S, Moles-Fernández A, Diez O, Nguyen-Dumont T, Southey MC, Hopper JL, Simard J, Dumont M, Soucy P, Meindl A, Schmutzler R, Schmidt MK, Adank MA, Andrulis IL, Hahnen E, Engel C, Lesueur F, Girard E, Neuhausen SL, Ziv E, Allen J, Easton DF, Scott RJ, Gorringe KL, James PA, Campbell IG. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. NPJ Breast Cancer. 2021 May 12;7(1):52. doi: 10.1038/s41523-021-00255-3. PMID: 33980861; PMCID: PMC8115524.
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NPJ Breast Cancer. 2021 May 12;7(1):52. doi: 10.1038/s41523-021-00255-3.

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

NPJ breast cancer

Na Li, Magnus Zethoven, Simone McInerny, Lisa Devereux, Yu-Kuan Huang, Niko Thio, Dane Cheasley, Sara Gutiérrez-Enríquez, Alejandro Moles-Fernández, 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, Irene L Andrulis, Eric Hahnen, Christoph Engel, Fabienne Lesueur, Elodie Girard, Susan L Neuhausen, Elad Ziv, Jamie Allen, Douglas F Easton, Rodney J Scott, Kylie L Gorringe, Paul A James, Ian G Campbell

Affiliations

  1. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia.
  3. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia.
  4. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  5. Lifepool, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  6. Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  7. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic, Australia.
  8. Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO); Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  9. Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  10. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
  11. Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia.
  12. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  13. Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Quebec, Canada.
  14. University of Munich, Campus Großhadern, Department of Gynecology and Obstetrics, Munich, Germany.
  15. Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany.
  16. Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Integrated Oncology (CIO), Cologne, Germany.
  17. Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
  18. Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  19. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  20. Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  21. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  22. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  23. Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
  24. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
  25. Inserm, U900, Institut Curie, PSL University, Mines ParisTech, Paris, France.
  26. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  27. Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
  28. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  29. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  30. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
  31. Discipline of Medical Genetics, The University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia.
  32. Division of Molecular Medicine, Pathology North, Newcastle, NSW, Australia.
  33. Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  34. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [email protected].
  35. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia. [email protected].
  36. Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia. [email protected].

PMID: 33980861 PMCID: PMC8115524 DOI: 10.1038/s41523-021-00255-3

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 studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

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