Department of Surgical and Oncological Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
Oncogene. 2012 Apr 26;31(17):2121-8. doi: 10.1038/onc.2011.408. Epub 2011 Sep 26.
Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited BC syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, are associated with moderate risk. Therefore, all of these known genes account for only 25% of the familial aggregation cases. Recently, genome wide association studies (GWAS) in BC revealed single nucleotide polymorphisms (SNPs) in five novel genes associated to susceptibility: TNRC9, FGFR2, MAP3K1, H19 and lymphocyte-specific protein 1 (LSP1). The most strongly associated SNP was in intron 2 of the FGFR2 gene that is amplified and overexpressed in 5-10% of BC. rs3803662 of TNRC9 gene has been shown to be the SNP with the strongest association with BC, in particular, this polymorphism seems to be correlated with bone metastases and estrogen receptor positivity. Relevant data indicate that SNP rs889312 in MAP3K1 is correlated with BC susceptibility only in BRCA2 mutation carriers, but is not associated with an increased risk in BRCA1 carriers. Finally, different SNPs in LSP1 and H19 and in minor genes probably were associated with BC risk. New susceptibility allelic variants associated with BC risk were recently discovered including potential causative genes involved in regulation of cell cycle, apoptosis, metabolism and mitochondrial functions. In conclusion, the identification of disease susceptibility loci may lead to a better understanding of the biological mechanism for BC to improve prevention, early detection and treatment.
乳腺癌（BC）是一种表现出家族聚集性的异质性疾病。家族连锁研究已经确定了 BRCA1、BRCA2、PTEN 和 TP53 等高外显率基因，这些基因负责遗传性 BC 综合征。此外，基于家族和基于人群的方法的结合表明，参与 DNA 修复的基因，如 CHEK2、ATM、BRIP 和 PALB2，与中度风险相关。因此，所有这些已知的基因仅占家族聚集病例的 25%。最近，BC 的全基因组关联研究（GWAS）揭示了与易感性相关的五个新基因中的单核苷酸多态性（SNP）：TNRC9、FGFR2、MAP3K1、H19 和淋巴细胞特异性蛋白 1（LSP1）。与 FGFR2 基因的内含子 2中最相关的 SNP 是扩增和过度表达的，在 5-10%的 BC 中。TNRC9 基因的 rs3803662 已被证明与 BC 具有最强的相关性，特别是这种多态性似乎与骨转移和雌激素受体阳性相关。相关数据表明，MAP3K1 中的 SNP rs889312 仅与 BRCA2 突变携带者的 BC 易感性相关，但与 BRCA1 携带者的风险增加无关。最后，LSP1 和 H19 中的不同 SNP 以及次要基因中的 SNP 可能与 BC 风险相关。最近发现了与 BC 风险相关的新易感等位基因变异，包括参与细胞周期、凋亡、代谢和线粒体功能调节的潜在致病基因。总之，疾病易感性基因座的鉴定可能有助于更好地了解 BC 的生物学机制，以改善预防、早期发现和治疗。
