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Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18-7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers.

Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

Titel:	Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.
Autor/in / Beteiligte Person:	Hu, C ; Nagaraj, AB ; Shimelis, H ; Montalban, G ; Lee, KY ; Huang, H ; Lumby, CA ; Na, J ; Susswein, LR ; Roberts, ME ; Marshall, ML ; Hiraki, S ; LaDuca, H ; Chao, E ; Yussuf, A ; Pesaran, T ; Neuhausen, SL ; Haiman, CA ; Kraft, P ; Lindstrom, S ; Palmer, JR ; Teras, LR ; Vachon, CM ; Yao, S ; Ong, I ; Nathanson, KL ; Weitzel, JN ; Boddicker, N ; Gnanaolivu, R ; Polley, EC ; Mer, G ; Cui, G ; Karam, R ; Richardson, ME ; Domchek, SM ; Yadav, S ; Hruska, KS ; Dolinsky, J ; Weroha, SJ ; Hart, SN ; Simard, J ; Masson, JY ; Pang, YP ; Couch, FJ
Zeitschrift:	Cancer research, Jg. 83 (2023-08-01), Heft 15, S. 2557-2571
Veröffentlichung:	Baltimore, Md. : American Association for Cancer Research ; <i>Original Publication</i>: Chicago [etc.], 2023
Medientyp:	academicJournal
ISSN:	1538-7445 (electronic)
DOI:	10.1158/0008-5472.CAN-22-2319
Schlagwort:	Female Humans Adenosine Triphosphate Genetic Predisposition to Disease Mutation, Missense Breast Neoplasms genetics DNA-Binding Proteins genetics Ovarian Neoplasms genetics Ovarian Neoplasms pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Cancer Res] 2023 Aug 01; Vol. 83 (15), pp. 2557-2571. MeSH Terms: Breast Neoplasms* / genetics ; DNA-Binding Proteins* / genetics ; Ovarian Neoplasms* / genetics ; Ovarian Neoplasms* / pathology ; Female ; Humans ; Adenosine Triphosphate ; Genetic Predisposition to Disease ; Mutation, Missense References: Cancer Treat Rev. 2019 Feb;73:1-9. (PMID: 30543930) ; Nat Genet. 2012 Apr 26;44(5):475-6; author reply 476. (PMID: 22538716) ; Front Biosci. 1998 Jun 17;3:D570-603. (PMID: 9632377) ; Mol Cancer Ther. 2013 Jun;12(6):865-77. (PMID: 23512992) ; Nucleic Acids Res. 2015 Nov 16;43(20):9835-55. (PMID: 26354865) ; EMBO J. 2006 Jan 11;25(1):222-31. (PMID: 16395335) ; Genet Med. 2020 Mar;22(3):622-632. (PMID: 31636395) ; J Med Genet. 2022 Dec;59(12):1206-1218. (PMID: 36162851) ; Am J Hum Genet. 2021 Mar 4;108(3):458-468. (PMID: 33609447) ; Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2202727119. (PMID: 36099300) ; PLoS One. 2011;6(9):e25632. (PMID: 21980511) ; Genet Med. 2019 Aug;21(8):1708-1718. (PMID: 30643217) ; J Natl Cancer Inst. 2021 Oct 1;113(10):1429-1433. (PMID: 33146377) ; Am J Hum Genet. 2018 Oct 4;103(4):498-508. (PMID: 30219179) ; Gynecol Oncol. 2017 Nov;147(2):375-380. (PMID: 28888541) ; Nucleic Acids Res. 2019 Nov 18;47(20):10662-10677. (PMID: 31586400) ; Nucleic Acids Res. 2016 Nov 2;44(19):9017-9030. (PMID: 27596592) ; Mol Cell Biol. 2013 Jan;33(2):387-95. (PMID: 23149936) ; N Engl J Med. 2021 Feb 4;384(5):428-439. (PMID: 33471991) ; J Med Genet. 2022 Jul;59(7):632-643. (PMID: 34844974) ; Cell Rep. 2018 Dec 18;25(12):3273-3282.e6. (PMID: 30566856) ; Hum Mutat. 2012 Jan;33(1):95-9. (PMID: 21990120) ; Breast Cancer Res Treat. 2014 Aug;147(1):133-43. (PMID: 25086635) ; Lancet Oncol. 2011 Sep;12(9):852-61. (PMID: 21862407) ; Nucleic Acids Res. 2002 Feb 15;30(4):1009-15. (PMID: 11842113) ; Mol Cell Biol. 2006 Nov;26(21):8075-86. (PMID: 16954385) ; Genet Med. 2015 May;17(5):405-24. (PMID: 25741868) ; Mol Cell. 2017 Sep 7;67(5):867-881.e7. (PMID: 28757209) ; N Engl J Med. 2021 Feb 4;384(5):440-451. (PMID: 33471974) ; Mutat Res. 1987 Jun;178(2):235-44. (PMID: 3587254) ; Nat Genet. 2010 May;42(5):410-4. (PMID: 20400964) ; J Biol Chem. 2003 Oct 31;278(44):42729-32. (PMID: 12912992) ; PLoS Genet. 2019 Oct 4;15(10):e1008355. (PMID: 31584931) ; J Clin Oncol. 2015 Sep 10;33(26):2901-7. (PMID: 26261251) ; Cancer Discov. 2018 Nov;8(11):1404-1421. (PMID: 30213835) ; J Biol Chem. 2003 Jan 24;278(4):2469-78. (PMID: 12427746) ; Cancer Discov. 2017 Sep;7(9):984-998. (PMID: 28588062) ; Mol Cell. 2021 Mar 4;81(5):1043-1057.e8. (PMID: 33421364) ; Am J Hum Genet. 2016 Oct 6;99(4):877-885. (PMID: 27666373) ; Genet Med. 2020 Feb;22(2):407-415. (PMID: 31406321) ; Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303. (PMID: 29788355) ; Proteins. 2016 Oct;84(10):1490-516. (PMID: 27348292) ; Nature. 2018 Oct;562(7726):217-222. (PMID: 30209399) ; Mol Cell Biol. 2001 Apr;21(8):2858-66. (PMID: 11283264) ; Am J Hum Genet. 2018 Feb 1;102(2):233-248. (PMID: 29394989) ; Nat Genet. 2011 Aug 07;43(9):879-882. (PMID: 21822267) ; JAMA Oncol. 2022 Mar 01;8(3):e216744. (PMID: 35084436) ; J Biol Chem. 2000 Sep 15;275(37):29100-6. (PMID: 10871607) ; Hum Mutat. 2016 Mar;37(3):235-41. (PMID: 26555599) ; Br J Cancer. 2008 Apr 22;98(8):1457-66. (PMID: 18349832) ; J Natl Cancer Inst. 2020 Dec 14;112(12):1242-1250. (PMID: 32107557) ; Breast Cancer Res Treat. 2011 Dec;130(3):1003-10. (PMID: 21750962) ; J Biol Chem. 2012 Jan 27;287(5):3366-80. (PMID: 22167183) ; Nat Genet. 2018 Jun;50(6):874-882. (PMID: 29785012) ; Genes Dev. 2001 Dec 15;15(24):3296-307. (PMID: 11751635) Grant Information: P30 ES013508 United States ES NIEHS NIH HHS; P50 CA116201 United States CA NCI NIH HHS; R35 CA253187 United States CA NCI NIH HHS Substance Nomenclature: 8L70Q75FXE (Adenosine Triphosphate) ; 0 (DNA-Binding Proteins) ; 0 (RAD51C protein, human) ; 0 (XRCC2 protein, human) Entry Date(s): Date Created: 20230530 Date Completed: 20230804 Latest Revision: 20240620 Update Code: 20240620 PubMed Central ID: PMC10390864

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Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.