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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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
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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