Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
JCI Insight. 2017 Sep 7;2(17). doi: 10.1172/jci.insight.95703.
Bone metastases (BoM) are a significant cause of morbidity in patients with estrogen receptor-positive (ER-positive) breast cancer; yet, characterizations of human specimens are limited. In this study, exome-capture RNA sequencing (ecRNA-seq) on aged (8-12 years), formalin-fixed, paraffin-embedded (FFPE), and decalcified cancer specimens was evaluated. Gene expression values and ecRNA-seq quality metrics from FFPE or decalcified tumor RNA showed minimal differences when compared with matched flash-frozen or nondecalcified tumors. ecRNA-seq was then applied on a longitudinal collection of 11 primary breast cancers and patient-matched synchronous or recurrent BoMs. Overtime, BoMs exhibited gene expression shifts to more Her2 and LumB PAM50 subtype profiles, temporally influenced expression evolution, recurrently dysregulated prognostic gene sets, and longitudinal expression alterations of clinically actionable genes, particularly in the CDK/Rb/E2F and FGFR signaling pathways. Taken together, this study demonstrates the use of ecRNA-seq on decade-old and decalcified specimens and defines recurrent longitudinal transcriptional remodeling events in estrogen-deprived breast cancers.
骨转移（BoM）是雌激素受体阳性（ER 阳性）乳腺癌患者发病率的重要原因；然而，对人体标本的特征描述有限。在这项研究中，对陈旧（8-12 年）、福尔马林固定、石蜡包埋（FFPE）和脱钙的癌症标本进行外显子组捕获 RNA 测序（ecRNA-seq）。与匹配的新鲜冷冻或非脱钙肿瘤相比，FFPE 或脱钙肿瘤 RNA 的基因表达值和 ecRNA-seq 质量指标差异最小。然后，对 11 例原发性乳腺癌和患者匹配的同步或复发性 BoM 的纵向样本进行 ecRNA-seq 分析。随着时间的推移，BoM 表现出向更多 Her2 和 LumB PAM50 亚型谱的基因表达转变，受时间影响的表达演变，复发失调的预后基因集，以及临床可操作基因的纵向表达改变，特别是在 CDK/Rb/E2F 和 FGFR 信号通路中。总之，这项研究展示了在十年以上和脱钙标本上使用 ecRNA-seq，并定义了雌激素剥夺性乳腺癌中反复出现的纵向转录重塑事件。
