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

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Standard

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. / ENIGMA Consortium; CIMBA Consortium.

I: Genetics in Medicine, Bind 24, Nr. 1, 2022, s. 119-129.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

ENIGMA Consortium & CIMBA Consortium 2022, 'Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants', Genetics in Medicine, bind 24, nr. 1, s. 119-129. https://doi.org/10.1016/j.gim.2021.08.016

APA

ENIGMA Consortium, & CIMBA Consortium (2022). Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. Genetics in Medicine, 24(1), 119-129. https://doi.org/10.1016/j.gim.2021.08.016

Vancouver

ENIGMA Consortium, CIMBA Consortium. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. Genetics in Medicine. 2022;24(1):119-129. https://doi.org/10.1016/j.gim.2021.08.016

Author

ENIGMA Consortium ; CIMBA Consortium. / Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. I: Genetics in Medicine. 2022 ; Bind 24, Nr. 1. s. 119-129.

Bibtex

@article{3eedb317f13d4525af5e7ef61e46d74b,
title = "Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants",
abstract = "Purpose: 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.",
keywords = "BRCA1, BRCA2, Cancer risks, Missense variants",
author = "Hongyan Li and Christoph Engel and {de la Hoya}, Miguel and Paolo Peterlongo and Drakoulis Yannoukakos and Luca Livraghi and Paolo Radice and Mads Thomassen and Hansen, {Thomas V.O.} and Gerdes, {Anne Marie} and Nielsen, {Henriette R.} and Caputo, {Sandrine M.} and Alberto Zambelli and Ake Borg and Angela Solano and Abigail Thomas and Parsons, {Michael T.} and Antoniou, {Antonis C.} and Goska Leslie and Xin Yang and Georgia Chenevix-Trench and Trinidad Caldes and Ava Kwong and Pedersen, {Inge S{\o}kilde} and Lautrup, {Charlotte K.} and John, {Esther M.} and Terry, {Mary Beth} and Hopper, {John L.} and Southey, {Melissa C.} and Andrulis, {Irene L.} and Marc Tischkowitz and Ramunas Janavicius and Boonen, {Susanne E.} and Lone Kroeldrup and Liliana Varesco and Ute Hamann and Ana Vega and Palmero, {Edenir I.} and Judy Garber and Marco Montagna and {Van Asperen}, {Christi J.} and Lenka Foretova and Greene, {Mark H.} and Tina Selkirk and Pal Moller and Toland, {Amanda E.} and Domchek, {Susan M.} and James, {Paul A.} and Heather Thorne and Eccles, {Diana M.} and {ENIGMA Consortium} and {CIMBA Consortium}",
note = "Publisher Copyright: {\textcopyright} 2021 American College of Medical Genetics and Genomics",
year = "2022",
doi = "10.1016/j.gim.2021.08.016",
language = "English",
volume = "24",
pages = "119--129",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

AU - Li, Hongyan

AU - Engel, Christoph

AU - de la Hoya, Miguel

AU - Peterlongo, Paolo

AU - Yannoukakos, Drakoulis

AU - Livraghi, Luca

AU - Radice, Paolo

AU - Thomassen, Mads

AU - Hansen, Thomas V.O.

AU - Gerdes, Anne Marie

AU - Nielsen, Henriette R.

AU - Caputo, Sandrine M.

AU - Zambelli, Alberto

AU - Borg, Ake

AU - Solano, Angela

AU - Thomas, Abigail

AU - Parsons, Michael T.

AU - Antoniou, Antonis C.

AU - Leslie, Goska

AU - Yang, Xin

AU - Chenevix-Trench, Georgia

AU - Caldes, Trinidad

AU - Kwong, Ava

AU - Pedersen, Inge Søkilde

AU - Lautrup, Charlotte K.

AU - John, Esther M.

AU - Terry, Mary Beth

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Andrulis, Irene L.

AU - Tischkowitz, Marc

AU - Janavicius, Ramunas

AU - Boonen, Susanne E.

AU - Kroeldrup, Lone

AU - Varesco, Liliana

AU - Hamann, Ute

AU - Vega, Ana

AU - Palmero, Edenir I.

AU - Garber, Judy

AU - Montagna, Marco

AU - Van Asperen, Christi J.

AU - Foretova, Lenka

AU - Greene, Mark H.

AU - Selkirk, Tina

AU - Moller, Pal

AU - Toland, Amanda E.

AU - Domchek, Susan M.

AU - James, Paul A.

AU - Thorne, Heather

AU - Eccles, Diana M.

AU - ENIGMA Consortium

AU - CIMBA Consortium

N1 - Publisher Copyright: © 2021 American College of Medical Genetics and Genomics

PY - 2022

Y1 - 2022

N2 - Purpose: 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.

AB - Purpose: 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.

KW - BRCA1

KW - BRCA2

KW - Cancer risks

KW - Missense variants

U2 - 10.1016/j.gim.2021.08.016

DO - 10.1016/j.gim.2021.08.016

M3 - Journal article

C2 - 34906479

AN - SCOPUS:85122352590

VL - 24

SP - 119

EP - 129

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 1

ER -

ID: 318696806