Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D.,Journal of the National Cancer Institute

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Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D.
Journal of the National Cancer Institute ( IF 9.9 ) Pub Date : 2020-02-28 , DOI: 10.1093/jnci/djaa030
Xin Yang ₁ , Honglin Song _{1,

2} , Goska Leslie ₁ , Christoph Engel ₃ , Eric Hahnen _{4,

5} , Bernd Auber ₆ , Judit Horváth ₇ , Karin Kast _{8,

9,

10} , Dieter Niederacher ₁₁ , Clare Turnbull ₁₂ , Richard Houlston ₁₂ , Helen Hanson ₁₂ , Chey Loveday ₁₂ , Jill S Dolinsky ₁₃ , Holly LaDuca ₁₃ , Susan J Ramus _{14,

15,

16} , Usha Menon ₁₇ , Adam N Rosenthal ₁₈ , Ian Jacobs _{18,

19,

20} , Simon A Gayther ₂₁ , Ed Dicks ₂ , Heli Nevanlinna ₂₂ , Kristiina Aittomäki ₂₃ , Liisa M Pelttari ₂₂ , Hans Ehrencrona _{24,

25} , Åke Borg ₂₆ , Anders Kvist ₂₆ , Barbara Rivera _{27,

28} , Thomas V O Hansen _{29,

30} , Malene Djursby ₃₀ , Andrew Lee ₁ , Joe Dennis ₁ , David D Bowtell _{31,

32} , Nadia Traficante _{31,

32} , Orland Diez _{33,

34} , Judith Balmaña _{35,

36} , Stephen B Gruber ₃₇ , Georgia Chenevix-Trench ₃₈ , kConFab Investigators ₃₉ , Allan Jensen ₄₀ , Susanne K Kjær _{40,

41} , Estrid Høgdall _{40,

42} , Laurent Castéra ₄₃ , Judy Garber ₄₄ , Ramunas Janavicius _{45,

46} , Ana Osorio _{47,

48} , Lisa Golmard ₄₉ , Ana Vega _{47,

50,

51} , Fergus J Couch ₅₂ , Mark Robson ₅₃ , Jacek Gronwald ₅₄ , Susan M Domchek ₅₅ , Julie O Culver ₅₆ , Miguel de la Hoya ₅₇ , Douglas F Easton _{1,

2} , William D Foulkes _{5,

8} , Marc Tischkowitz _{5,

9} , Alfons Meindl ₅₈ , Rita K Schmutzler _{4,

5,

59} , Paul D P Pharoah _{1,

2} , Antonis C Antoniou ₁

Affiliation

Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Faculty of Medicine and University Hospital Cologne, Center for Familial Breast and Ovarian Cancer, University of Cologne, Cologne, Germany.
Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology, University of Cologne, Cologne, Germany.
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Institute of Human Genetics, University of Münster, Münster, Germany.
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Gynecology and Obstetrics, Heinrich-Heine University Düsseldorf, University Hospital Düsseldorf, Düsseldorf, Germany.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Ambry Genetics, Aliso Viejo, Canada.
School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia.
Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.
Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Women's Cancer, Institute for Women's Health, University College London, London, UK.
University of New South Wales, Sydney, New South Wales, Australia.
University of Manchester, Manchester, UK.
Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Department of Clinical Genetics and Pathology, Laboratory Medicine, Office for Medical Services, Region Skåne, Lund, Sweden.
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Gerald Bronfman Dept Oncology, Jewish General Hospital, McGill University and Lady Davis Institute, Montréal, QC, Canada.
Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Clinical Genetics Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Sir Peter MacCallum, Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Oncogenetics Group, Vall dHebron Institute of Oncology, Barcelona, Spain.
Clinical and Molecular Genetics Area, University Hospital Vall dHebron, Barcelona, Spain.
Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer.
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Gynaecology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Department of Pathology, Molecular Unit, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Cancer Biology and Genetics, Normandy Centre for Genomic and Personalized Medicine, François Baclesse Center, Inserm U1245, Caen, France.
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania.
State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
Centro de Investigación en Red de Enfermedades Raras, Madrid, Spain.
Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
Institut Curie, Paris Sciences Lettres Research University, Service de Génétique, Paris, France.
Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, Clinical Genetics Service, New York, NY, USA.
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

BACKGROUND The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

中文翻译：

卵巢癌和乳腺癌风险与 RAD51C 和 RAD51D 的致病性变异相关。

背景本研究的目的是准确评估 RAD51C 和 RAD51D 致病性变异携带者的年龄特异性输卵管卵巢癌 (TOC) 和乳腺癌 (BC) 风险。方法我们分析了 6178 个家族的数据，其中 125 个家族在 RAD51C 中存在致病性变异； 6690 个家族，其中 60 个家族具有 RAD51D 致病变异。使用复杂的分离分析来估计 TOC 和 BC 的相对和累积风险，以模拟家庭中的癌症遗传模式，同时调整每个家庭的确定模式。所有统计检验都是双面的。结果 RAD51C 和 RAD51D 的致病变异均与 TOC 相关（RAD51C RR = 7.55，95%CI：5.60-10.19，p = 5 × 10-40；RAD51D RR = 7.60，95%CI：5.61-10.30，p = 5 × 10-39) 和 BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4;RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002)。对于 RAD51C 和 RAD51D，有人建议 TOC RR 随着年龄的增长而增加，直到 60 岁左右，此后下降。 RAD51C 致病性变异携带者在 80 岁时发生 TOC 的估计累积风险为 11% (95%CI:6-21%)，RAD51D 致病性变异携带者为 13% (95%CI:7-23%)。 RAD51C 致病性变异携带者发展为 BC 至 80 岁的估计累积风险为 21%（95%CI：15-29%），RAD51D 致病变异携带者为 20%（95%CI：14-28%）。 RAD51C/D 致病性变异携带者的 TOC 和 BC 风险因癌症家族史而异，对于有两名一级亲属诊断为 TOC 的携带者，TOC 的风险可能高达 32-36%；或 BC 为 44-46%，对于有两名一级亲属诊断为 BC 的携带者。结论这些估计将促进 RAD51C 和 RAD51D 致病性变异携带者的遗传咨询，并证明将 RAD51C 和 RAD51D 纳入癌症风险预测模型的合理性。

更新日期：2020-02-28

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