Li, Na ORCID: 0000-0003-1578-9561, Zethoven, Magnus, McInerny, Simone, Devereux, Lisa ORCID: 0000-0003-2435-5888, Huang, Yu-Kuan, Thio, Niko, Cheasley, Dane ORCID: 0000-0002-1170-4690, Gutierrez-Enriquez, Sara ORCID: 0000-0002-1711-6101, Moles-Fernandez, Alejandro, Diez, Orland, Nguyen-Dumont, Tu, Southey, Melissa C., Hopper, John L., Simard, Jacques ORCID: 0000-0001-6906-3390, Dumont, Martine, Soucy, Penny, Meindl, Alfons, Schmutzler, Rita, Schmidt, Marjanka K., Adank, Muriel A., Andrulis, Irene L., Hahnen, Eric, Engel, Christoph ORCID: 0000-0002-7247-282X, Lesueur, Fabienne ORCID: 0000-0001-7404-4549, Girard, Elodie, Neuhausen, Susan L., Ziv, Elad, Allen, Jamie, Easton, Douglas F., Scott, Rodney J., Gorringe, Kylie L., James, Paul A. and Campbell, Ian 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). BERLIN: NATURE RESEARCH. ISSN 2374-4677

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, NaUNSPECIFIEDorcid.org/0000-0003-1578-9561UNSPECIFIED
Zethoven, MagnusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McInerny, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devereux, LisaUNSPECIFIEDorcid.org/0000-0003-2435-5888UNSPECIFIED
Huang, Yu-KuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thio, NikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheasley, DaneUNSPECIFIEDorcid.org/0000-0002-1170-4690UNSPECIFIED
Gutierrez-Enriquez, SaraUNSPECIFIEDorcid.org/0000-0002-1711-6101UNSPECIFIED
Moles-Fernandez, AlejandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen-Dumont, TuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDorcid.org/0000-0001-6906-3390UNSPECIFIED
Dumont, MartineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soucy, PennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adank, Muriel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Lesueur, FabienneUNSPECIFIEDorcid.org/0000-0001-7404-4549UNSPECIFIED
Girard, ElodieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziv, EladUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, JamieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, Rodney J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorringe, Kylie L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
James, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, Ian G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-606495
DOI: 10.1038/s41523-021-00255-3
Journal or Publication Title: npj Breast Cancer
Volume: 7
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2374-4677
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOLOGOUS RECOMBINATION REPAIR; GENOMIC INSTABILITY; DNA-REPAIR; MUTANT P53; MUTATION; BRCA1; EXPRESSION; PREDICTOR; DISCOVERY; POLYPOSISMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60649

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