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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.
Li, Na; Zethoven, Magnus; McInerny, Simone; Devereux, Lisa; Huang, Yu-Kuan; Thio, Niko; Cheasley, Dane; Gutiérrez-Enríquez, Sara; Moles-Fernández, Alejandro; Diez, Orland; 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; Andrulis, Irene L; Hahnen, Eric; Engel, Christoph; Lesueur, Fabienne; Girard, Elodie; Neuhausen, Susan L; Ziv, Elad; Allen, Jamie; Easton, Douglas F; Scott, Rodney J; Gorringe, Kylie L; James, Paul A; Campbell, Ian G.
Afiliación
  • Li N; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Zethoven M; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia.
  • McInerny S; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia.
  • Devereux L; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Huang YK; Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Thio N; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia.
  • Cheasley D; Lifepool, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Gutiérrez-Enríquez S; Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Moles-Fernández A; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic, Australia.
  • Diez O; Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Nguyen-Dumont T; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.
  • Southey MC; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia.
  • Hopper JL; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO); Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • Simard J; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO); Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • Dumont M; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO); Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • Soucy P; Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • Meindl A; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
  • Schmutzler R; Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia.
  • Schmidt MK; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
  • Adank MA; Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia.
  • Andrulis IL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Hahnen E; Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Quebec, Canada.
  • Engel C; Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Quebec, Canada.
  • Lesueur F; Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Quebec, Canada.
  • Girard E; University of Munich, Campus Großhadern, Department of Gynecology and Obstetrics, Munich, Germany.
  • Neuhausen SL; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany.
  • Ziv E; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Integrated Oncology (CIO), Cologne, Germany.
  • Allen J; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
  • Easton DF; Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  • Scott RJ; Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Gorringe KL; Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • James PA; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • Campbell IG; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
NPJ Breast Cancer ; 7(1): 52, 2021 May 12.
Article en En | MEDLINE | ID: mdl-33980861
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Idioma: En Revista: NPJ Breast Cancer Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Idioma: En Revista: NPJ Breast Cancer Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos