Sistema de Salut de Catalunya
Institut Català de la Salut
[Li N] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Zethoven M] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [McInerny S] Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Devereux L] Lifepool, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Huang YK] Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic, Australia. [Thio N] Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Gutiérrez-Enríquez S, Moles-Fernández A] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2022-01-12T17:00:02Z
2022-01-12T17:00:02Z
2021-04-12
Càncer de mama; Genètica del càncer; Mutació
Cáncer de mama; Genética del cáncer; Mutación
Breast cancer; Cancer genetics; Mutation
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.
Article
Published version
English
Mama - Càncer - Prognosi; Diàtesi; Malalties congènites; DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms; Other subheadings::Other subheadings::/diagnosis; PHENOMENA AND PROCESSES::Genetic Phenomena::Genotype::Genetic Predisposition to Disease; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama; Otros calificadores::Otros calificadores::/diagnóstico; FENÓMENOS Y PROCESOS::fenómenos genéticos::genotipo::predisposición genética a la enfermedad
Nature Research
npj Breast Cancer;7
https://doi.org/10.1038/s41523-021-00255-3
info:eu-repo/grantAgreement/ES/PE2013-2016/PI16%2F01218
info:eu-repo/grantAgreement/ES/PE2017-2020/PI19%2F01303
info:eu-repo/grantAgreement/ES/PE2013-2016/CP16%2F00034
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3440]
