生物谷报道：在《美国人类遗传学杂志》（American Journal of Human Genetics）最近刊登的一项研究中，一个国际科研团队发现，FGFR2和TNRC9基因突变会显著增加带有BRCA基因突变的妇女患乳腺癌的几率。
乳腺癌是女性乳腺最常见的恶性肿瘤之一，它的诊断和治疗是当前医学研究的热点。科学家已查明，BRCA1与BRCA2基因的突变很大程度上增加了女性患有乳腺癌的可能性。在正常情况下，这两种基因可传递控制细胞繁殖的信息。如果它们出现变异，细胞就会无节制地繁殖，导致癌症形成。但BRCA1 和BRCA2在预测乳腺癌家族性风险上却不能令人满意，因为携带BRCA1与BRCA2基因突变的人群相对很少。
新的研究识别出了与乳腺癌基因易感性相关的其它基因——FGFR2 和TNRC9，以前这两个基因曾被发现与乳腺癌有明显关系。新研究表明，FGFR2和TNRC9上的单核苷酸多态性会显著增大体内含有BRCA基因突变的妇女患乳腺癌的风险，如果体内同时存在这两种基因，患乳腺癌的几率将会高达70％。
研究人员希望能够通过遗传测试来更好预测女性将会患上乳腺癌的几率，特别是有家族性遗传史的女性。新发现同时也将对治理乳腺癌具有十分重要的意义，这些基因的识别将为乳腺癌发病原因研究开辟新的途径。(科学网 于乃森/编译)
The American Journal of Human Genetics, Volume 82, Issue 4, 937-948, 20 March 2008
doi:10.1016/j.ajhg.2008.02.008
Article
Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Antonis C. Antoniou1, , , Amanda B. Spurdle2, Olga M. Sinilnikova3, 4, Sue Healey2, Karen A. Pooley1, 5, Rita K. Schmutzler6, Beatrix Versmold6, Christoph Engel7, Alfons Meindl8, Norbert Arnold9, Wera Hofmann10, Christian Sutter11, Dieter Niederacher12, Helmut Deissler13, Trinidad Caldes14, Kati Kämpjärvi15, Heli Nevanlinna15, Jacques Simard16, Jonathan Beesley2, Xiaoqing Chen2, the Kathleen Cuningham Consortium for Research into Familial Breast Cancer17, Susan L. Neuhausen18, Timothy R. Rebbeck19, Theresa Wagner20, Henry T. Lynch21, Claudine Isaacs22, Jeffrey Weitzel23, Patricia A. Ganz24, Mary B. Daly25, Gail Tomlinson26, Olufunmilayo I. Olopade27, Joanne L. Blum28, Fergus J. Couch29, Paolo Peterlongo30, Siranoush Manoukian31, Monica Barile32, Paolo Radice30, Csilla I. Szabo33, Lutecia H. Mateus Pereira34, 65, Mark H. Greene35, Gad Rennert36, Flavio Lejbkowicz36, Ofra Barnett-Griness36, Irene L. Andrulis37, 38, 39, Hilmi Ozcelik38, 39, OCGN37, Anne-Marie Gerdes40, Maria A. Caligo41, Yael Laitman42, Bella Kaufman43, Roni Milgrom42, Eitan Friedman42, 43, The Swedish BRCA1 and BRCA2 study collaborators44, Susan M. Domchek45, Katherine L. Nathanson45, Ana Osorio46, Gemma Llort47, Roger L. Milne48, Javier Benítez46, 48, Ute Hamann49, Frans B.L. Hogervorst50, Peggy Manders51, Marjolijn J.L. Ligtenberg52, Ans M.W. van den Ouweland53, The DNA-HEBON collaborators44, Susan Peock1, Margaret Cook1, Radka Platte1, D. Gareth Evans54, Rosalind Eeles55, Gabriella Pichert56, Carol Chu57, Diana Eccles58, Rosemarie Davidson59, Fiona Douglas60, EMBRACE1, Andrew K. Godwin25, Laure Barjhoux3, 4, Sylvie Mazoyer4, Hagay Sobol61, Violaine Bourdon61, François Eisinger61, Agnès Chompret62, 66, Corinne Capoulade63, Brigitte Bressac-de Paillerets63, Gilbert M. Lenoir63, Marion Gauthier-Villars64, Claude Houdayer64, Dominique Stoppa-Lyonnet64, GEMO, Georgia Chenevix-Trench2, Douglas F. Easton1, on behalf of CIMBA
1 Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK
2 Queensland Institute of Medical Research, Brisbane, Australia
3 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
4 Laboratoire de Génétique Moléculaire, Signalisation et Cancer, UMR5201 CNRS, Université Lyon 1, Lyon, France
5 Cancer Research UK, Human Cancer Genetics Group, Department of Oncology, University of Cambridge, UK
6 Department of Obstetrics and Gynaecology, Division of Molecular Gynaeco-Oncology, University of Cologne, Germany
7 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
8 Department of Obstetrics and Gynaecology, Technical University, Munich, Germany
9 Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany
10 Institute of Human Genetics, Charite-University Medical Centre, Berlin, Germany
11 Institute of Human Genetics, University of Heidelberg, Germany
12 Molecular Genetics Laboratory, Department of Obstetrics and Gynaecology, University of Düsseldorf, Germany
13 Department of Obstetrics and Gynaecology, University of Ulm, Germany
14 Hospital Clinico San Carlos, Madrid, Spain
15 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland
16 Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Quebec and Laval University
17 Peter MacCallum Cancer Institute, Melbourne, Australia
18 Department of Epidemiology, University of California, Irvine, CA, USA
19 Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA
20 University of Vienna, Vienna, Austria
21 Creighton University, Omaha, NE, USA
22 Fisher Center for Familial Cancer Research, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
23 City of Hope National Medical Center, Duarte, CA, USA
24 UCLA Schools of Medicine & Public Health, and the UCLA Familial Cancer Registry of the Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA
25 Fox Chase Cancer Center, Philadelphia, PA, USA
26 University of Texas, Southwestern, Dallas, TX, USA
27 University of Chicago, Chicago, IL, USA
28 Baylor-Sammons Cancer Center, Dallas, Texas, USA
29 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
30 Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori and IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
31 Medical Genetics Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
32 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
33 Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
34 Laboratory of Population Genetics, US National Cancer Institute, National Institutes of Health, Rockville, MD, USA
35 Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA
36 CHS National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel
37 Ontario Cancer Genetics Network, Cancer Care Ontario, and Department of Molecular Genetics, University of Toronto, Ontario, Canada
38 Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
39 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada
40 Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Denmark
41 Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy
42 The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical center, Tel-Hashomer, Israel
43 Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel
44 See Acknowledgments
45 Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
46 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain
47 Genetic Counselling Unit, Prevention and Cancer Control Service, Institut Català d'Oncologia, Barcelona, Spain
48 Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain
49 Deutsches Krebsforschungszentrum, Heidelberg, Germany
50 Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
51 Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
52 Department of Human Genetics and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
53 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
54 Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK
55 Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, United Kingdom
56 Clinical Genetics, Guy's Hospital, London, UK
57 Yorkshire Regional Genetics Service, Leeds, UK
58 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
59 Ferguson-Smith Centre for Clinical Genetics, Glasgow, UK
60 Institute of Human Genetics, Centre for Life, Newcastle upon Tyne, UK
61 INSERM UMR599, Institut Paoli-Calmettes, Département d'Oncologie Génétique, Marseille 13275, France
62 Oncological Genetics, Department of Medicine, Institut Gustave Roussy, Villejuif, France
63 CNRS FRE2939, Department of Genetics, Institut Gustave Roussy, Villejuif, France
64 Institut Curie, Genetics Department, Université Paris-Descartes, France
Corresponding author
65 Present address: University of Miami, Sylvester Cancer Center, Miami, FL, USA.
66 Deceased.
Abstract
Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20–1.45, ptrend = 1.7 × 10−8 and HR = 1.12, 95% CI: 1.02–1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06–1.20, ptrend = 5 × 10−5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.
