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

Hongyan Li; Christoph Engel; Miguel de la Hoya; Paolo Peterlongo; Drakoulis Yannoukakos; Luca Livraghi; Paolo Radice; Mads Thomassen; Thomas V. O. Hansen; Anne-Marie Gerdes; Henriette R. Nielsen; Sandrine M. Caputo; Alberto Zambelli; Ake Borg; Angela Solano; Abigail Thomas; Michael T. Parsons; Antonis C. Antoniou; Goska Leslie; Xin Yang; Georgia Chenevix-Trench; Trinidad Caldes; Ava Kwong; Inge Søkilde Pedersen; Charlotte K. Lautrup; Esther M. John; Mary Beth Terry; John L. Hopper; Melissa C. Southey; Irene L. Andrulis; Marc Tischkowitz; Ramunas Janavicius; Susanne E. Boonen; Lone Kroeldrup; Liliana Varesco; Ute Hamann; Ana Vega; Edenir I. Palmero; Judy Garber; Marco Montagna; Christi J. Van Asperen; Lenka Foretova; Mark H. Greene; Tina Selkirk; Pal Moller; Amanda E. Toland; Susan M. Domchek; Paul A. James; Heather Thorne; Diana M. Eccles; Sarah M. Nielsen; Siranoush Manoukian; Barbara Pasini; Maria A. Caligo; Conxi Lazaro; Judy Kirk; Barbara Wappenschmidt; Amanda B. Spurdle; Fergus J. Couch; Rita Schmutzler; David E Goldgar; ENIGMA consortium; CIMBA 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

Hongyan Li, Christoph Engel, Miguel de la Hoya, Paolo Peterlongo, Drakoulis Yannoukakos, Luca Livraghi, Paolo Radice, Mads Thomassen, Thomas V. O. Hansen, Anne-Marie Gerdes, Henriette R. Nielsen, Sandrine M. Caputo, Alberto Zambelli, Ake Borg, Angela Solano, Abigail Thomas, Michael T. Parsons, Antonis C. Antoniou, Goska Leslie, Xin YangGeorgia Chenevix-Trench, Trinidad Caldes, Ava Kwong, Inge Søkilde Pedersen, Charlotte K. Lautrup, Esther M. John, Mary Beth Terry, John L. Hopper, Melissa C. Southey, Irene L. Andrulis, Marc Tischkowitz, Ramunas Janavicius, Susanne E. Boonen, Lone Kroeldrup, Liliana Varesco, Ute Hamann, Ana Vega, Edenir I. Palmero, Judy Garber, Marco Montagna, Christi J. Van Asperen, Lenka Foretova, Mark H. Greene, Tina Selkirk, Pal Moller, Amanda E. Toland, Susan M. Domchek, Paul A. James, Heather Thorne, Diana M. Eccles, Sarah M. Nielsen, Siranoush Manoukian, Barbara Pasini, Maria A. Caligo, Conxi Lazaro, Judy Kirk, Barbara Wappenschmidt, Amanda B. Spurdle, Fergus J. Couch, Rita Schmutzler, David E Goldgar^*, ENIGMA consortium, CIMBA Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

11 Citations (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.

Original language	English
Journal	Genetics in Medicine
Volume	24
Issue number	1
Pages (from-to)	119-129
Number of pages	11
ISSN	1098-3600
DOIs	https://doi.org/10.1016/j.gim.2021.08.016
Publication status	Published - Jan 2022

Bibliographical note

Keywords

BRCA1
BRCA2
Cancer risks
Missense variants

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10.1016/j.gim.2021.08.016

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170303/pdf/nihms-1858554.pdf

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Li, H., Engel, C., de la Hoya, M., Peterlongo, P., Yannoukakos, D., Livraghi, L., Radice, P., Thomassen, M., Hansen, T. V. O., Gerdes, A-M., Nielsen, H. R., Caputo, S. M., Zambelli, A., Borg, A., Solano, A., Thomas, A., Parsons, M. T., Antoniou, A. C., Leslie, G., ... 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. Advance online publication. https://doi.org/10.1016/j.gim.2021.08.016

@article{8cc27e8f140c4597aedf06010614dc87,

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 Eccles, {Diana M.} and Nielsen, {Sarah M.} and Siranoush Manoukian and Barbara Pasini and Caligo, {Maria A.} and Conxi Lazaro and Judy Kirk and Barbara Wappenschmidt and Spurdle, {Amanda B.} and Couch, {Fergus J.} and Rita Schmutzler and Goldgar, {David E} and {ENIGMA consortium} and {CIMBA 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 = "Nature Publishing Group",

number = "1",

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Li, H, Engel, C, de la Hoya, M, Peterlongo, P, Yannoukakos, D, Livraghi, L, Radice, P, Thomassen, M, Hansen, TVO, Gerdes, A-M, Nielsen, HR, Caputo, SM, Zambelli, A, Borg, A, Solano, A, Thomas, A, Parsons, MT, Antoniou, AC, Leslie, G, Yang, X, Chenevix-Trench, G, Caldes, T, Kwong, A, Pedersen, IS, Lautrup, CK, John, EM, Terry, MB, Hopper, JL, Southey, MC, Andrulis, IL, Tischkowitz, M, Janavicius, R, Boonen, SE, Kroeldrup, L, Varesco, L, Hamann, U, Vega, A, Palmero, EI, Garber, J, Montagna, M, Van Asperen, CJ, Foretova, L, Greene, MH, Selkirk, T, Moller, P, Toland, AE, Domchek, SM, James, PA, Thorne, H, Eccles, DM, Nielsen, SM, Manoukian, S, Pasini, B, Caligo, MA, Lazaro, C, Kirk, J, Wappenschmidt, B, Spurdle, AB, Couch, FJ, Schmutzler, R, Goldgar, DE, 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, vol. 24, no. 1, pp. 119-129. https://doi.org/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. / Li, Hongyan; Engel, Christoph; de la Hoya, Miguel et al.
In: Genetics in Medicine, Vol. 24, No. 1, 01.2022, p. 119-129.

Research output: Contribution to journal › Journal article › Research › 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 - Eccles, Diana M.

AU - Nielsen, Sarah M.

AU - Manoukian, Siranoush

AU - Pasini, Barbara

AU - Caligo, Maria A.

AU - Lazaro, Conxi

AU - Kirk, Judy

AU - Wappenschmidt, Barbara

AU - Spurdle, Amanda B.

AU - Couch, Fergus J.

AU - Schmutzler, Rita

AU - Goldgar, David E

AU - ENIGMA consortium

AU - CIMBA 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

UR - http://www.scopus.com/inward/record.url?scp=85122352590&partnerID=8YFLogxK

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

Bibliographical note

Keywords

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