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Article: Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

TitleRisks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants
Authors
KeywordsBRCA1
BRCA2
Cancer risks
Missense variants
Issue Date2022
PublisherElsevier Inc. The Journal's web site is located at https://www.journals.elsevier.com/genetics-in-medicine
Citation
Genetics In Medicine, 2022, v. 24 n. 1, p. 119-129 How to Cite?
AbstractPurpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.
Persistent Identifierhttp://hdl.handle.net/10722/310136
ISSN
2023 Impact Factor: 6.6
2023 SCImago Journal Rankings: 2.697

 

DC FieldValueLanguage
dc.contributor.authorLi, H-
dc.contributor.authorEngel, C-
dc.contributor.authorde la Hoya, M-
dc.contributor.authorPeterlongo, P-
dc.contributor.authorYannoukakos, D-
dc.contributor.authorLivraghi, L-
dc.contributor.authorRadice, P-
dc.contributor.authorThomassen, M-
dc.contributor.authorHansen, TVO-
dc.contributor.authorGerdes, AM-
dc.contributor.authorNielsen, HR-
dc.contributor.authorCaputo, SM-
dc.contributor.authorZambelli, A-
dc.contributor.authorBorg, A-
dc.contributor.authorSolano, A-
dc.contributor.authorThomas, A-
dc.contributor.authorParsons, MT-
dc.contributor.authorAntoniou, AC-
dc.contributor.authorLeslie, G-
dc.contributor.authorYang, X-
dc.contributor.authorChenevix-Trench, G-
dc.contributor.authorCaldes, T-
dc.contributor.authorKwong, A-
dc.contributor.authorPedersen, IS-
dc.contributor.authorLautrup, CK-
dc.contributor.authorJohn, EM-
dc.contributor.authorTerry, MB-
dc.contributor.authorHopper, JL-
dc.contributor.authorSouthey, MC-
dc.contributor.authorAndrulis, IL-
dc.contributor.authorTischkowitz, M-
dc.contributor.authorJanavicius, R-
dc.contributor.authorBoonen, SE-
dc.contributor.authorKroeldrup, L-
dc.contributor.authorVaresco, L-
dc.contributor.authorHamann, U-
dc.contributor.authorVega, A-
dc.contributor.authorPalmero, EI-
dc.contributor.authorGarber, J-
dc.contributor.authorMontagna, M-
dc.contributor.authorVan Asperen, CJ-
dc.contributor.authorForetova, L-
dc.contributor.authorGreene, MH-
dc.contributor.authorSelkirk, T-
dc.contributor.authorMoller, P-
dc.contributor.authorToland, AE-
dc.contributor.authorDomchek, SM-
dc.contributor.authorJames, PA-
dc.contributor.authorThorne, H-
dc.contributor.authorEccles, DM-
dc.contributor.authorNielsen, SM-
dc.contributor.authorManoukian, S-
dc.contributor.authorPasini, B-
dc.contributor.authorCaligo, MA-
dc.contributor.authorLazaro, C-
dc.contributor.authorKirk, J-
dc.contributor.authorWappenschmidt, B-
dc.contributor.authorSpurdle, AB-
dc.contributor.authorCouch, FJ-
dc.contributor.authorSchmutzler, R-
dc.contributor.authorGoldgar, DE-
dc.date.accessioned2022-01-24T02:24:23Z-
dc.date.available2022-01-24T02:24:23Z-
dc.date.issued2022-
dc.identifier.citationGenetics In Medicine, 2022, v. 24 n. 1, p. 119-129-
dc.identifier.issn1098-3600-
dc.identifier.urihttp://hdl.handle.net/10722/310136-
dc.description.abstractPurpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.-
dc.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at https://www.journals.elsevier.com/genetics-in-medicine-
dc.relation.ispartofGenetics In Medicine-
dc.subjectBRCA1-
dc.subjectBRCA2-
dc.subjectCancer risks-
dc.subjectMissense variants-
dc.titleRisks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants-
dc.typeArticle-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.authorityKwong, A=rp01734-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.gim.2021.08.016-
dc.identifier.pmid34906479-
dc.identifier.scopuseid_2-s2.0-85122352590-
dc.identifier.hkuros331540-
dc.identifier.volume24-
dc.identifier.issue1-
dc.identifier.spage119-
dc.identifier.epage129-
dc.publisher.placeUnited States-

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