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

doi:10.1016/j.gim.2021.08.016

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

16 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Genetics in Medicine
Vol/bind	24
Nummer	1
Sider (fra-til)	119-129
Antal sider	11
ISSN	1098-3600
DOI	https://doi.org/10.1016/j.gim.2021.08.016
Status	Udgivet - jan. 2022
Udgivet eksternt	Ja

Adgang til dokumentet

10.1016/j.gim.2021.08.016

Citationsformater

@article{98347c73a53c42c1b37724e16545369a,

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 Anne-Marie Gerdes 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 Nielsen, {Sarah M} and {ENIGMA Consortium}",

year = "2022",

month = jan,

doi = "10.1016/j.gim.2021.08.016",

language = "English",

volume = "24",

pages = "119--129",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "1",

}

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.
I: Genetics in Medicine, Bind 24, Nr. 1, 01.2022, s. 119-129.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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 - Nielsen, Sarah M

AU - ENIGMA Consortium

PY - 2022/1

Y1 - 2022/1

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

SN - 1098-3600

VL - 24

SP - 119

EP - 129

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -

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

Abstract

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