Department of Medical Genetics, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester M13 0JH, UK.
J Med Genet. 2010 Feb;47(2):126-31. doi: 10.1136/jmg.2009.067256. Epub 2009 Jul 16.
Recent candidate and genome-wide association studies have identified variants altering susceptibility to breast cancer.
To establish the relevance of these variants to breast cancer risk in familial breast cancer cases both with and without BRCA1 or BRCA2 (BRCA1/2) mutations.
A cohort of unrelated individuals with breast cancer due to the presence of either BRCA1 (121) or BRCA2 mutations (109) and individuals with familial breast cancer not due to BRCA1/2 mutations (722) were genotyped using Taqman SNP Genotyping Assays. Allele frequencies were compared with an ethnically and gender-matched group (436).
A synonymous variant (Ser51) in TOX3 (previously TNRC9) was associated with an increased risk of breast cancer (OR=1.82, p<0.001) in BRCA2 mutation carriers. The associations for FGFR2 (OR=1.20, p=0.046), TOX3 (OR=1.5, p<0.001), MAP3K1 (OR=1.26 p=0.03), CASP8 (OR=0.73 p=0.02) and the chromosome 8-associated SNP (OR=1.31, p=0.004) were replicated in individuals without BRCA1/2 mutations. In addition, homozygote carriers of MAP3K1 variants were shown to have a significantly lower Manchester Score (mean 13.8-17.6, p=0.003), whereas individuals carrying one or two copies of the FGFR2 variant had a higher Manchester Score (mean 17.5-17.9, p=0.01).
This study confirms that susceptibility variants in FGFR2, TOX3 and MAP3K1 and on chromosome 8q are all associated with increased risk of cancer in individuals with a family history of breast cancer, whereas CASP8 is protective in this context. The level of risk is dependent on the strength of the family history and the presence of a BRCA1/2 mutation and contributes to the understanding of the use of these variants in clinical risk prediction.
最近的候选基因和全基因组关联研究已经确定了改变乳腺癌易感性的变异。
确定这些变异与携带 BRCA1 或 BRCA2（BRCA1/2）突变的家族性乳腺癌病例以及不携带 BRCA1/2 突变的家族性乳腺癌病例的乳腺癌风险的相关性。
使用 Taqman SNP 基因分型检测对由于 BRCA1（121）或 BRCA2 突变（109）而患有乳腺癌的无关联个体以及不由于 BRCA1/2 突变而患有家族性乳腺癌的个体（722）进行基因分型。比较等位基因频率与种族和性别匹配的组（436）。
TOX3（先前称为 TNRC9）中的同义变体（Ser51）与 BRCA2 突变携带者的乳腺癌风险增加相关（OR=1.82，p<0.001）。FGFR2（OR=1.20，p=0.046）、TOX3（OR=1.5，p<0.001）、MAP3K1（OR=1.26，p=0.03）、CASP8（OR=0.73，p=0.02）和与 8 号染色体相关的 SNP（OR=1.31，p=0.004）的关联在不携带 BRCA1/2 突变的个体中得到了复制。此外，MAP3K1 变体的纯合子携带者的曼彻斯特评分明显较低（平均值为 13.8-17.6，p=0.003），而携带 FGFR2 变体的一个或两个拷贝的个体的曼彻斯特评分较高（平均值为 17.5-17.9，p=0.01）。
本研究证实，FGFR2、TOX3 和 MAP3K1 中的易感变体以及 8 号染色体上的变体均与携带乳腺癌家族史的个体的癌症风险增加相关，而 CASP8 在这种情况下具有保护作用。风险水平取决于家族史的强度和 BRCA1/2 突变的存在，并有助于理解这些变体在临床风险预测中的应用。
