- Title
- Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
- Creator
- Li, Na; Zethoven, Magnus; Nguyen-Dumont, Tu; Southey, Melissa C.; Hopper, John L.; Simard, Jacques; Dumont, Martine; Soucy, Penny; Meindl, Alfons; Schmutzler, Rita; Schmidt, Marjanka K.; Adank, Muriel A.; McInerny, Simone; Andrulis, Irene L.; Hahnen, E; Engel, C; Lesueur, F; Girard, E; Neuhausen, SL; Ziv, E; Allen, J; Easton, DF; Scott, Rodney J.; Devereux, Lisa; Gorringe, KL; James, PA; Campbell, IG; Huang, Yu-Kuan; Thio, Niko; Cheasley, Dane; Gutiérrez-Enríquez, Sara; Moles-Fernández, Alejandro; Diez, Orland
- Relation
- NHMRC.1023698 http://purl.org/au-research/grants/nhmrc/1023698
- Relation
- npj Breast Cancer Vol. 7, Issue 1, no. 52
- Publisher Link
- http://dx.doi.org/10.1038/s41523-021-00255-3
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2021
- Description
- 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.
- Subject
- gene NTHL1; breast cancer; immunohistochemistry; coding variants; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1457566
- Identifier
- uon:45355
- Identifier
- ISSN:2374-4677
- Rights
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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