Agyemang Kojo, Johansen Allan M, Barker Grayson W, Pennison Michael J, Sheffield Kimberly, Jimenez Hugo, Blackman Carl, Sharma Sambad, Fordjour Patrick A, Singh Ravi, Cook Katherine L, Lin Hui-Kuan, Zhang Wei, Lo Hui-Wen, Watabe Kounosuke, Sun Peiqing, Langefeld Carl D, Pasche Boris
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA.
Department of Thoracic Medicine, School of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.
NPJ Breast Cancer. 2022 Jul 19;8(1):84. doi: 10.1038/s41523-022-00446-6.
There is growing evidence that germline mutations in certain genes influence cancer susceptibility, tumor evolution, as well as clinical outcomes. Identification of a disease-causing genetic variant enables testing and diagnosis of at-risk individuals. For breast cancer, several genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 act as high- to moderate-penetrance cancer susceptibility genes. Genotyping of these genes informs genetic risk assessment and counseling, as well as treatment and management decisions in the case of high-penetrance genes. TGFBR16A (rs11466445) is a common variant of the TGF-β receptor type I (TGFBR1) that has a global minor allelic frequency (MAF) of 0.051 according to the 1000 Genomes Project Consortium. It is emerging as a high frequency, low penetrance tumor susceptibility allele associated with increased cancer risk among several cancer types. The TGFBR16A allele has been associated with increased breast cancer risk in women, OR 1.15 (95% CI 1.01-1.31). Functionally, TGFBR16A promotes breast cancer cell proliferation, migration, and invasion through the regulation of the ERK pathway and Rho-GTP activation. This review discusses current findings on the genetic, functional, and mechanistic associations between TGFBR16A and breast cancer risk and proposes future directions as it relates to genetic association studies and mechanisms of action for tumor growth, metastasis, and immune suppression.
越来越多的证据表明，某些基因的种系突变会影响癌症易感性、肿瘤演变以及临床结果。识别致病基因变异能够对高危个体进行检测和诊断。对于乳腺癌而言，诸如BRCA1、BRCA2、PALB2、ATM和CHEK2等多个基因可作为高至中度外显率的癌症易感基因。对这些基因进行基因分型有助于进行遗传风险评估与咨询，以及针对高外显率基因的治疗和管理决策。TGFBR16A（rs11466445）是I型转化生长因子-β受体（TGFBR1）的一个常见变异体，根据千人基因组计划联盟的数据，其全球次要等位基因频率（MAF）为0.051。它正逐渐成为一种高频、低外显率的肿瘤易感等位基因，与多种癌症类型中增加的癌症风险相关。TGFBR16A等位基因与女性乳腺癌风险增加相关，比值比为1.15（95%置信区间1.01 - 1.31）。在功能上，TGFBR16A通过调节ERK途径和Rho - GTP激活来促进乳腺癌细胞的增殖、迁移和侵袭。本综述讨论了目前关于TGFBR16A与乳腺癌风险之间的遗传、功能和机制关联的研究结果，并就其与遗传关联研究以及肿瘤生长、转移和免疫抑制作用机制相关的未来方向提出了建议。
