Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Breast Cancer Res. 2021 Jan 6;23(1):1. doi: 10.1186/s13058-020-01379-3.
Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease.
We performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor's matched primary.
Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1, and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common-including outlier gains in TP63 (n = 5 cases [42%]), NTRK3 (n = 5 [42%]), NTRK2 (n = 4 [33%]), PAX3 (n = 4 [33%]), FGFR4 (n = 3 [25%]), and TERT (n = 3 [25%]). Recurrent losses involved ESR1 (n = 5 [42%]), RELN (n = 5 [42%]), SFRP4 (n = 4 [33%]), and FOSB (n = 4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers.
Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common ESR1-depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.
内分泌治疗耐药是晚期雌激素受体（ER）阳性乳腺癌的标志。在这项研究中，我们旨在确定内分泌耐药疾病中的获得性基因组变化。
我们对 12 例长期雌激素剥夺后的局部复发进行了 12 个局部复发的 DNA/RNA 杂交捕获测序，并鉴定了与每个肿瘤匹配的原发性相比获得的基因组变化。
尽管距离原发性病变最长可达 7 年，但大多数复发肿瘤仍具有相似的固有转录和拷贝数特征。只有两个基因 AKAP9 和 KMT2C 在一个以上的复发病例中发现了单核苷酸变异（SNV）富集。在单个病例中发现的富集突变包括转录调节剂中的 SNVs，如 ARID1A、TP53、FOXO1、BRD1、NCOA1 和 NCOR2，一个局部复发获得了三个 PIK3CA 突变。与 DNA 水平的变化相反，我们发现常见的复发性异常 mRNA 表达改变——包括 5 例（42%）TP63 的异常获得，NTRK3（n=5 [42%]），NTRK2（n=4 [33%]），PAX3（n=4 [33%]），FGFR4（n=3 [25%]）和 TERT（n=3 [25%]）。复发性缺失涉及 ESR1（n=5 [42%]），RELN（n=5 [42%]），SFRP4（n=4 [33%]）和 FOSB（n=4 [33%]）。ESR1 缺失的复发病例存在共同的转录重塑事件，包括 PROM1 和其他基底癌标志物的上调。
综上所述，本研究定义了长期雌激素剥夺疾病中的获得性基因组变化；强调了纵向 RNA 分析的重要性；并确定了一种常见的 ESR1 缺失的内分泌耐药乳腺癌亚型，具有基底样转录重编程。
