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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/97871f690ed34ff7804d2d19d439847c
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spelling	oai:doaj.org-article:97871f690ed34ff7804d2d19d439847c2021-12-02T17:16:04ZEvaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects10.1038/s41523-021-00255-32374-4677https://doaj.org/article/97871f690ed34ff7804d2d19d439847c2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00255-3https://doaj.org/toc/2374-4677Abstract 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.Na LiMagnus ZethovenSimone McInernyLisa DevereuxYu-Kuan HuangNiko ThioDane CheasleySara Gutiérrez-EnríquezAlejandro Moles-FernándezOrland DiezTu Nguyen-DumontMelissa C. SoutheyJohn L. HopperJacques SimardMartine DumontPenny SoucyAlfons MeindlRita SchmutzlerMarjanka K. SchmidtMuriel A. AdankIrene L. AndrulisEric HahnenChristoph EngelFabienne LesueurElodie GirardSusan L. NeuhausenElad ZivJamie AllenDouglas F. EastonRodney J. ScottKylie L. GorringePaul A. JamesIan G. CampbellNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
description	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.
format	article
author	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
author_facet	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
author_sort	Na Li
title	Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
title_short	Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
title_full	Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
title_fullStr	Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
title_full_unstemmed	Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
title_sort	evaluation of the association of heterozygous germline variants in nthl1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/97871f690ed34ff7804d2d19d439847c
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Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

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