Abstract
PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
| Original language | English |
|---|---|
| Pages (from-to) | 674-685 |
| Journal | Journal of Clinical Oncology |
| Volume | 38 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2020 Mar 1 |
Bibliographical note
Funding Information:We thank the members of the PALB2-IG for their very helpful comments and suggestions. We are grateful to all clinicians, genetics counselors, and other health care professionals who have contributed families with PALB2 to PROMPT. The City of Hope Clinical Cancer Genomics Community Research Network was supported by award number RC4A153828 (principal investigator, J.N.W.) from the National Cancer Institute (NCI) and the Office of the Director, National Institutes of Health (NIH). J.N.W. was also supported by the Breast Cancer Research Foundation and the Dr Norman & Melinda Payson Professorship in Medical Oncology. T.S. was supported by the NCI grant K08CA234394. A.M.D. is supported by Cancer Research UK grant C8197/A16565. The HEBCS study was supported by a Helsinki University Hospital research grant, the Sigrid Jusélius Foundation, and the Finnish Cancer Society. K.B.M.C. is supported by grant G.A044.10 from the Fund for Scientific Research–Flanders. SWE-BRCA (The Swedish BRCA1 & BRCA2 Study Collaborators): Gothenburg, Sahlgrenska University Hospital: Zakaria Einbeigi; Linköping University Hospital: Marie Stenmark-Askmalm and Ekaterina Kuchinskaya; Lund University Hospital: Hans Ehrencrona, Therese Törngren, Anders Kvist, and Åke Borg; Stockholm, Karolinska University Hospital: Brita Arver, Annika Lindblom, and Emma Tham; Umeå University Hospital: Beatrice Melin; and Uppsala University Hospital: Ylva Paulsson-Karlsson. Z.K., P.K., J.S., and M.J. were supported by grants from the Ministry of Health of the Czech Republic (NV16-29959A) and Charles University projects PROGRES Q28/LF1 and SVV2019/260367. We thank clinical geneticists Kamila Vesela, Ales Panczak, and Jaroslav Kotlas from the Institute of Biology and Medical Genetics and Michal Vocka from the Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague for their valuable contribution to the study. This study was supported by Research Council of Lithuania grant SEN18/2015. A.S.G.L. was supported by grants from the National Medical Research Council (NMRC) of Singapore (NMRC/0763/2003, NMRC/1194/2008, NMRC/CBRG/0034/2013). S.N. is partially supported by the Morris and Horowitz Families Endowed Professorship. P.C. and J.L.B. represent the WECARE Study Collaborative Group, which is supported by NCI grants CA083178, CA097397, CA114236, and CA129639. S.D. is funded by Susan G Komen. F.C. was supported by NIH grants CA128978 and CA116167, an NIH Specialized Program of Research Excellence in Breast Cancer grant (CA116201), and the Breast Cancer Research Foundation. This study was partially supported by grants from Associazione Italiana per la Ricerca sul Cancro to P.Pe. (AIRC-IG #4017) and P.R. (AIRC-IG #15547) and from Ricerca Finalizzata–Bando 2010 from Ministero della Salute, Italy (C.T. and P.Pe.), and by funds from the Italian citizens who allocated a 5/1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori according to Italian laws (INT-Institutional Strategic Projects “5x1000”; S.M.). L.O. was supported by Associazione Italiana per la Ricerca sul Cancro grant AIRC-IG 2018-ID. 21389 and Italian Ministry of Education, Universities and Research–Dipartimenti di Eccellenza-L. 232/2016. D.G.E. is supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215–20007). We thank all the collaborating cancer clinics of the French National Study GENESIS (GENE SISters); the GENESIS principal investigators D. Stoppa-Lyonnet and N. Andrieu; the Investigation Platform (PIGE), S. Eon-Marchais, M.G. Dondon, D. Le Gal, J. Beauvallet, N. Mebirouk, and E. Cavaciuti; as well as L. Barjhoux (Biological Resource Centre). The GENESIS study was supported by the Ligue Nationale Contre le Cancer (grants PRE05/DSL and PRE07/DSL), the Institut National du Cancer (INCa grant No. b2008-029/LL-LC), and the Site de Recherche Intégrée sur le Cancer (grant INCa-DGOS-4654).
Funding Information:
E.R.M. acknowledges funding from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), and Cancer Research UK Cambridge Cancer Centre. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. The University of Cambridge has received salary support for E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from National Health and Medical Research Council (NHMRC), the National Breast Cancer Foundation, Cancer Australia, and NIH) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation and previously by NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. We thank the Breast Cancer Family Registry (BCFR), which is funded by the NCI, NIH. T.N.-D. is supported by a Career Development Fellowship from the National Breast Cancer Foundation (Australia, ECF-17-001). We thank Eric Rosenthal and the team at Myriad Genetics for their help in recruiting patients. This work was supported by NCI grant UM1 CA164920. The content of this article does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the BCFR. I.L.A. holds the Anne and Max Tanenbaum Chair in Molecular Medicine at Mount Sinai Hospital and the University of Toronto. The Australian site of the BCFR was also supported by the NHMRC of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation, and the Victorian Breast Cancer Research Consortium. This work was also supported by the NHMRC (project grant APP1029974) and the Victorian Breast Cancer Research Consortium. M.So. is an NHMRC Senior Research Fellow, and J.L.H. is an NHMRC Senior Principal Research Fellow. T.P. is supported in part by the Ingram Professorship and the Kleeberg Foundation. R.W. is supported by the Academy of Finland (project grant 318337 and Center of Excellence grant 251314), the Finnish Cancer Foundation, the Sigrid Jusélius Foundation, the University of Oulu, and the special Government Funding of Oulu University Hospital grants. K.Py. is supported by Academy of Finland Research Fellow grant 314183 and the Finnish Cancer Foundation. A.Ma. is supported by special Government Funding of Kuopio University Hospital grants, the Cancer Fund of North Savo, the Finnish Cancer Foundation, and the strategic funding of the University of Eastern Finland. The MyBrCa study was funded by research grants from the Wellcome trust (203477/Z/16/Z), Ministry of Higher Education to University Malaya (UM.c/Hir/MOHe/06), Estée Lauder group of companies, Sime Darby Foundation, PETRONAS Foundation, Cancer Research UK (c1287/a16563, c8197/a16565, and c12292/a20861), and the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 634935 (BriDgeS), and the PerSPectiVe project was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation. The University of Miami Caribbean Women’s Cancer Study was funded by the Susan G Komen Foundation. P.P. receives salary support from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve. S.H.L.G. is funded by the CDMRP Ovarian Cancer program (W81XWH-18-1-0072). J.B. was supported by the Carlos III National Health Institute funded by FEDER funds–a way to build Europe (PI16/11363). W.D.F. is funded by Susan G Komen and CIHR Foundation Grant FDN 148390. The analysis and data management for this project was support by Cancer Research UK grant C12292/A20861. M.T. was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n.310018.
Publisher Copyright:
© 2019 by American Society of Clinical Oncology.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
Subject classification (UKÄ)
- Cancer and Oncology
