Molecular characterisation of aromatase inhibitor-resistant advanced breast cancer: the phenotypic effect of ESR1 mutations
Molecular characterisation of aromatase inhibitor-resistant advanced breast cancer: the phenotypic effect of ESR1 mutations
复制标题
DOI：
10.1038/s41416-018-0345-x
复制
发表时间：
2019-01-22
影响因子：
8.8
通讯作者：
Dowsett, Mitch
中科院分区：
文献类型：
--
作者：
Lopez-Knowles, Elena;Pearson, Alex;Dowsett, Mitch
背景：在英国，每年有数千名乳腺癌患者对芳香酶抑制剂（AIs）产生耐药性。合理的治疗需要改进耐药疾病的分子特征。材料和方法：在48例患者AI治疗前和AI进展时，通过配对活检评估了16个关键乳腺癌基因198个区域的突变景观和覆盖关键通路的209个基因的RNA表达。在另外5例在AI中进展的esr1突变肿瘤中评估了结果的有效性。结果：在41对配对中鉴定出89个突变（PIK3CA占27%，CDH1占20%）。ESR1 （n = 5）、ERBB2 （n = 1）和MAP2K4 （n = 1）仅在次级样本中发生突变。抗ai肿瘤之间的基因表达异质性非常高，几乎没有明显的模式。然而，在ESR1突变的ai耐药肿瘤中，四种经典雌激素调节基因（ERGs）的表达比ESR1野生型肿瘤高7倍，这一发现在第二组ESR1突变的肿瘤中得到证实。在ESR1野生型抗ai肿瘤中，ERG的表达仍然受到抑制，并且与增殖中的恢复不耦合。结论：ai耐药疾病之间存在主要的基因型和表型异质性。ESR1突变似乎在耐药肿瘤中驱动雌激素调节过程。
BACKGROUND: Several thousand breast cancer patients develop resistance to aromatase inhibitors (AIs) each year in the UK. Rational treatment requires an improved molecular characterisation of resistant disease.MATERIALS AND METHODS: The mutational landscape of 198 regions in 16 key breast cancer genes and RNA expression of 209 genes covering key pathways was evaluated in paired biopsies before AI treatment and at progression on AI from 48 patients. Validity of findings was assessed in another five ESR1-mutated tumours progressing on AI.RESULTS: Eighty-nine mutations were identified in 41 matched pairs (PIK3CA in 27%; CDH1 in 20%). ESR1 (n = 5), ERBB2 (n = 1) and MAP2K4 (n = 1) had mutations in the secondary sample only. There was very high heterogeneity in gene expression between AI-resistant tumours with few patterns apparent. However, in the ESR1-mutated AI-resistant tumours, expression of four classical oestrogen-regulated genes (ERGs) was sevenfold higher than in ESR1 wild-type tumours, a finding confirmed in the second set of ESR1-mutated tumours. In ESR1 wild-type AI-resistant tumours ERG expression remained suppressed and was uncoupled from the recovery seen in proliferation.CONCLUSIONS: Major genotypic and phenotypic heterogeneity exists between AI-resistant disease. ESR1 mutations appear to drive oestrogen-regulated processes in resistant tumours.