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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  • ENIGMA Consortium
  • CIMBA Consortium

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.

OriginalsprogEngelsk
TidsskriftGenetics in Medicine
Vol/bind24
Udgave nummer1
Sider (fra-til)119-129
Antal sider11
ISSN1098-3600
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank the families who participated in the study. This work was funded by grants from the French National Cancer Institute INCa BCB (2013-1-BCB-01-531 ICH-1) and from the French Ligue contre le cancer 92. A.E.T. wishes to thank Hayley Cassingham, Leigha Senter, and Kevin Sweet who were instrumental in consenting of study participants and data collection and funding from The Ohio State University Comprehensive Cancer Center.

Funding Information:
The work of A.B.S. and M.T.P. was supported by the Australian National Health and Medical Research funding (ID1177524). E.I.P. was supported by Barretos Cancer Hospital, FINEP - CT-INFRA (02/2010), and a National Council of Technological and Scientific Development (CNPq) scholarship. We wish to thank members of the Center of Molecular Diagnosis, Oncogenetics Department, and Molecular Oncology Research Center of Barretos Cancer Hospital for their contributions to the study. M.d.l.H was supported by grants from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI15/00059 and PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union). A.V. was supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII) through Research Activity Intensification Program (contract grants: INT15/00070, INT16/00154, INT17/00133, INT20/00071) and through Centro de Investigación Biomédica en Red de Enfermedades Raras (ACCI 2016: ER17P1AC7112/2018); by Autonomous Government of Galicia (Consolidation and structuring program: IN607B); and by the Fundación Mutua Madrileña (call 2018).We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan and Bogota, Colombia. I.L.A., M.B.T., and E.M.J. were supported by grant UM1 CA164920 from the US National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast Cancer Family Registry. P.R. was supported by funds from the Italian Association for Cancer Research (IG number 22093).The work of P.P. was supported by the Italian Association for Cancer Research funding IG-16732. B.P. was supported by the DSM-UniTO Excellence Project n. D15D18000410001. The contribution of F.J.C. was supported by National Institutes of Health grants R35 CA253187, R01 CA225662, and R01 CA116167; a specialized program of research excellence in breast cancer (P50 CA116201); and the Breast Cancer Research Foundation. S.D. was supported by the Breast Cancer Research Foundation.The work of A.C.A., G.L., and X.Y. were supported by Cancer Research United Kingdom grants C12292/A20861 and PPRPGM-Nov20/100002. S.M.C. thanks the clinicians and biologists ( Supplemental Table 2 ) involved in the French Unicancer Genetic Group for their cooperation.

Funding Information:
The work of A.B.S. and M.T.P. was supported by the Australian National Health and Medical Research funding (ID1177524). E.I.P. was supported by Barretos Cancer Hospital, FINEP - CT-INFRA (02/2010), and a National Council of Technological and Scientific Development (CNPq) scholarship. We wish to thank members of the Center of Molecular Diagnosis, Oncogenetics Department, and Molecular Oncology Research Center of Barretos Cancer Hospital for their contributions to the study. M.d.l.H was supported by grants from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI15/00059 and PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union). A.V. was supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII) through Research Activity Intensification Program (contract grants: INT15/00070, INT16/00154, INT17/00133, INT20/00071) and through Centro de Investigación Biomédica en Red de Enfermedades Raras (ACCI 2016: ER17P1AC7112/2018); by Autonomous Government of Galicia (Consolidation and structuring program: IN607B); and by the Fundación Mutua Madrileña (call 2018).We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan and Bogota, Colombia. I.L.A. M.B.T. and E.M.J. were supported by grant UM1 CA164920 from the US National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast Cancer Family Registry. P.R. was supported by funds from the Italian Association for Cancer Research (IG number 22093).The work of P.P. was supported by the Italian Association for Cancer Research funding IG-16732. B.P. was supported by the DSM-UniTO Excellence Project n. D15D18000410001. The contribution of F.J.C. was supported by National Institutes of Health grants R35 CA253187, R01 CA225662, and R01 CA116167; a specialized program of research excellence in breast cancer (P50 CA116201); and the Breast Cancer Research Foundation. S.D. was supported by the Breast Cancer Research Foundation.The work of A.C.A. G.L. and X.Y. were supported by Cancer Research United Kingdom grants C12292/A20861 and PPRPGM-Nov20/100002. S.M.C. thanks the clinicians and biologists ( Supplemental Table 2) involved in the French Unicancer Genetic Group for their cooperation. We thank the families who participated in the study. This work was funded by grants from the French National Cancer Institute INCa BCB (2013-1-BCB-01-531 ICH-1) and from the French Ligue contre le cancer 92. A.E.T. wishes to thank Hayley Cassingham, Leigha Senter, and Kevin Sweet who were instrumental in consenting of study participants and data collection and funding from The Ohio State University Comprehensive Cancer Center. Conceptualization: D.E.G. A.B.S. F.J.C. R.S. B.W.; Data Curation: A.E.T. P.P. P.R. T.C. L.L. E.I.P. A.K. H.T. P.J. B.W. C.E. M.T. T.H. E.J. M.B.T. M.T.P. I.A. S.C. C.L. H.N. J.G. M.M. M.S. A.S. A.Z. A.G. U.H. S.D. S.N. S.M.C. B.P. M.C.S. J.K. G.C.T. J.H. P.M. R.J. L.K. D.Y. S.E.B. L.V. A.V. T.S. D.E.G. C.J.V.A. G.L. A.T. L.F; Formal Analysis: H.L. D.E.G; Funding Acquisition: F.J.C. A.S.; Methodology: D.E.G. A.C.A. X.Y. M.T.P. H.L.; Writing-original draft: D.E.G.; Writing-review and editing: H.L. C.E. M.d.l.H. P.P. D.Y. L.L. P.R. M.T. T.V.O.H. A.M.G. H.R.N. S.M.C. A.Z. A.B. A.S. A.T. M.T.P. A.C.A. G.L. X.Y. G.C.T. T.C. A.K. I.S.P. C.K.L. E.M.J. M.B.T. J.L.H. M.C.S. I.L.A. M.T. R.J. S.E.B. L.K. L.V. U.H. A.V. E.I.P. J.G. M.M. C.J.V.A. L.F. M.H.G. T.S. P.M. A.E.T. S.M.D. P.J. H.T. D.M.E. S.M.N. S.M. B.P. M.A.C. C.L. J.K. B.W. F.J.C. R.S. D.E.G. ENIGMA Consortium, CIMBA Consortium. This study was covered under Amendment to Project P1051 (PI: A.BS.) approved by the Human Research Ethics Committee at QIMR Berghofer, Brisbane, Australia, on October 7, 2020. All patients gave consent to have their data used for research purposes, and all studies received local Ethics Committee approvals. Data from all centers were de-identified before analysis at the coordinating center. BRCA Exchange. Accessed February 15, 2021. https://brcaexchange.org/. HCI Priors database. Huntsman Cancer Institute. Accessed February 15, 2021. http://priors.hci.utah.edu/PRIORS/BRCA/viewer.php?gene=BRCA1.

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