生物谷報(bào)道：在《美國(guó)人類遺傳學(xué)雜志》（American  Journal  of  Human  Genetics）最近刊登的一項(xiàng)研究中,，一個(gè)國(guó)際科研團(tuán)隊(duì)發(fā)現(xiàn),，F(xiàn)GFR2和TNRC9基因突變會(huì)顯著增加帶有BRCA基因突變的婦女患乳腺癌的幾率。

乳腺癌是女性乳腺最常見(jiàn)的惡性腫瘤之一,，它的診斷和治療是當(dāng)前醫(yī)學(xué)研究的熱點(diǎn),。科學(xué)家已查明,，BRCA1與BRCA2基因的突變很大程度上增加了女性患有乳腺癌的可能性,。在正常情況下，這兩種基因可傳遞控制細(xì)胞繁殖的信息,。如果它們出現(xiàn)變異,，細(xì)胞就會(huì)無(wú)節(jié)制地繁殖，導(dǎo)致癌癥形成,。但BRCA1  和BRCA2在預(yù)測(cè)乳腺癌家族性風(fēng)險(xiǎn)上卻不能令人滿意,，因?yàn)閿y帶BRCA1與BRCA2基因突變的人群相對(duì)很少。

新的研究識(shí)別出了與乳腺癌基因易感性相關(guān)的其它基因——FGFR2  和TNRC9，以前這兩個(gè)基因曾被發(fā)現(xiàn)與乳腺癌有明顯關(guān)系,。新研究表明,，F(xiàn)GFR2和TNRC9上的單核苷酸多態(tài)性會(huì)顯著增大體內(nèi)含有BRCA基因突變的婦女患乳腺癌的風(fēng)險(xiǎn)，如果體內(nèi)同時(shí)存在這兩種基因,，患乳腺癌的幾率將會(huì)高達(dá)70％,。

研究人員希望能夠通過(guò)遺傳測(cè)試來(lái)更好預(yù)測(cè)女性將會(huì)患上乳腺癌的幾率，特別是有家族性遺傳史的女性,。新發(fā)現(xiàn)同時(shí)也將對(duì)治理乳腺癌具有十分重要的意義,，這些基因的識(shí)別將為乳腺癌發(fā)病原因研究開(kāi)辟新的途徑。(科學(xué)網(wǎng)  于乃森/編譯)

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.