转移性乳腺癌中雌激素受体编码基因或变异
2019-11-19 抗癌健康网
专注健康 关爱生命据《自然—遗传学》上的两项独立研究显示,在某些转移性乳腺癌病例中,负责编码雌激素受体的基因会发生变异。这意味着雌激素受体对抗药物或对某些转移性乳腺癌病例具有疗效。
Sarat Chandarlapaty等人选取了36个对激素疗法产生抗性的转移性乳腺癌肿瘤,对其中的230种基因进行测序,在9个肿瘤中发现ESR1基因突变。他们分析了44个转移性乳腺癌肿瘤中的ESR1基因,发现其中5个肿瘤存在基因突变。
在另一项研究中,Arul Chinnaiyan等人对11个肿瘤进行外显子组测序,在6个肿瘤中发现ESR1基因突变。两项研究都通过培养细胞展示了在缺少雌激素时变异雌激素受体的激活以及变异雌激素受体面对抗雌激素疗法的反应。(生物谷Bioon.com)
生物谷推荐的英文摘要
Nature Genetics doi:10.1038/ng.2822
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer
Weiyi Toy, Yang Shen, Helen Won, Bradley Green, Rita A Sakr, Marie Will, Zhiqiang Li, Kinisha Gala, Sean Fanning, Tari A King, Clifford Hudis, David Chen, Tetiana Taran, Gabriel Hortobagyi, Geoffrey Greene, Michael Berger, José Baselga & Sarat Chandarlapaty
Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.
doi:10.1038/ng.2823
Activating ESR1 mutations in hormone-resistant metastatic breast cancer
Dan R Robinson, Yi-Mi Wu, Pankaj Vats, Fengyun Su, Robert J Lonigro, Xuhong Cao, Shanker Kalyana-Sundaram, Rui Wang, Yu Ning, Lynda Hodges, Amy Gursky, Javed Siddiqui, Scott A Tomlins, Sameek Roychowdhury, Kenneth J Pienta, Scott Y Kim, J Scott Roberts, James M Rae, Catherine H Van Poznak, Daniel F Hayes, Rashmi Chugh, Lakshmi P Kunju, Moshe Talpaz, Anne F Schott & Arul M Chinnaiyan
Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.