Antoniou Antonis C, Spurdle Amanda B, Sinilnikova Olga M, Healey Sue, Pooley Karen A, Schmutzler Rita K, Versmold Beatrix, Engel Christoph, Meindl Alfons, Arnold Norbert, Hofmann Wera, Sutter Christian, Niederacher Dieter, Deissler Helmut, Caldes Trinidad, Kämpjärvi Kati, Nevanlinna Heli, Simard Jacques, Beesley Jonathan, Chen Xiaoqing, Neuhausen Susan L, Rebbeck Timothy R, Wagner Theresa, Lynch Henry T, Isaacs Claudine, Weitzel Jeffrey, Ganz Patricia A, Daly Mary B, Tomlinson Gail, Olopade Olufunmilayo I, Blum Joanne L, Couch Fergus J, Peterlongo Paolo, Manoukian Siranoush, Barile Monica, Radice Paolo, Szabo Csilla I, Pereira Lutecia H Mateus, Greene Mark H, Rennert Gad, Lejbkowicz Flavio, Barnett-Griness Ofra, Andrulis Irene L, Ozcelik Hilmi, Gerdes Anne-Marie, Caligo Maria A, Laitman Yael, Kaufman Bella, Milgrom Roni, Friedman Eitan, Domchek Susan M, Nathanson Katherine L, Osorio Ana, Llort Gemma, Milne Roger L, Benítez Javier, Hamann Ute, Hogervorst Frans B L, Manders Peggy, Ligtenberg Marjolijn J L, van den Ouweland Ans M W, Peock Susan, Cook Margaret, Platte Radka, Evans D Gareth, Eeles Rosalind, Pichert Gabriella, Chu Carol, Eccles Diana, Davidson Rosemarie, Douglas Fiona, Godwin Andrew K, Barjhoux Laure, Mazoyer Sylvie, Sobol Hagay, Bourdon Violaine, Eisinger François, Chompret Agnès, Capoulade Corinne, Bressac-de Paillerets Brigitte, Lenoir Gilbert M, Gauthier-Villars Marion, Houdayer Claude, Stoppa-Lyonnet Dominique, Chenevix-Trench Georgia, Easton Douglas F
Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK.
Am J Hum Genet. 2008 Apr;82(4):937-48. doi: 10.1016/j.ajhg.2008.02.008. Epub 2008 Mar 20.
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, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 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, p(trend) = 5 x 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.
BRCA1和BRCA2的种系突变会带来较高的乳腺癌风险。然而，有证据表明，这些风险会受到家族中聚集的其他遗传或环境因素的影响。最近一项全基因组关联研究表明，FGFR2（rs2981582）、TNRC9（rs3803662）和MAP3K1（rs889312）单核苷酸多态性（SNP）的常见等位基因与普通人群中乳腺癌风险增加有关。为了研究这些基因座是否也与BRCA1和BRCA2突变携带者的乳腺癌风险相关，我们对来自23项研究的10358名突变携带者样本中的这些SNP进行了基因分型。SNP rs2981582和rs889312的次要等位基因各自与BRCA2突变携带者的乳腺癌风险增加相关（每等位基因风险比[HR]=1.32，95%可信区间：1.20 - 1.45，p趋势=1.7×10⁻⁸；HR = 1.12，95%可信区间：1.02 - 1.24，p趋势=0.02），但在BRCA1携带者中并非如此。rs3803662与BRCA1和BRCA2突变携带者的乳腺癌风险增加相关（在BRCA1和BRCA2合并样本中，每等位基因HR = 1.13，95%可信区间：1.06 - 1.20，p趋势=5×10⁻⁵）。这些基因座在BRCA2突变携带者的乳腺癌风险上似乎存在相乘作用。BRCA1和BRCA2携带者中FGFR2和MAP3K1 SNP效应的差异表明BRCA1和BRCA2乳腺癌肿瘤生物学存在差异，并证实了BRCA1突变携带者中乳腺癌的独特性质。
