Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options. Tumor exome profiling has allowed to successfully establish targeted therapeutic strategies in the clinical management of cholangiocarcinoma (CCA). Still, whether liquid biopsy profiling could inform on BTC biology and patient management is unknown. In order to test this and generate novel insight into BTC biology, we analyzed the molecular landscape of 128 CCA patients, using a 394-gene NGS panel (Foundation Medicine). Among them, 32 patients had matched circulating tumor (ct) DNA and tumor DNA samples, where both samples were profiled. In both tumor and liquid biopsies, we identified an increased frequency of alterations in genes involved in genome integrity or chromatin remodeling, including ARID1A (15%), PBRM1 (9%), and BAP1 (14%), which were validated using an in-house-developed immunohistochemistry panel. ctDNA and tumor DNA showed variable concordance, with a significant correlation in the total number of detected variants, but some heterogeneity in the detection of actionable mutations. FGFR2 mutations were more frequently identified in liquid biopsies, whereas KRAS alterations were mostly found in tumors. All IDH1 mutations detected in tumor DNA were also identified in liquid biopsies. These findings provide novel insights in the concordance between the tumor and liquid biopsies genomic landscape in a large cohort of patients with BTC and highlight the complementarity of both analyses when guiding therapeutic prescription.

中文翻译：

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胆道癌的分子谱揭示了循环肿瘤 DNA 和组织肿瘤 DNA 之间不同的基因组景观

胆道癌（BTC）是一种异质性恶性肿瘤，由于肿瘤的侵袭性和对当前有限治疗方案的反应不佳，预后不佳。肿瘤外显子组分析可以在胆管癌 (CCA) 的临床管理中成功建立靶向治疗策略。尽管如此，液体活检分析是否可以为 BTC 生物学和患者管理提供信息尚不清楚。为了测试这一点并产生对 BTC 生物学的新见解，我们使用 394 基因 NGS panel（Foundation Medicine）分析了 128 名 CCA 患者的分子状况。其中，32 名患者拥有匹配的循环肿瘤 (ct) DNA 和肿瘤 DNA 样本，并对这两个样本进行了分析。在肿瘤和液体活检中，我们发现参与基因组完整性或染色质重塑的基因的改变频率增加，包括 ARID1A (15%)、PBRM1 (9%) 和 BAP1 (14%)，这些基因使用 in -内部开发的免疫组织化学面板。ctDNA 和肿瘤 DNA 显示出不同的一致性，在检测到的变异总数上存在显着相关性，但在检测可操作突变方面存在一些异质性。FGFR2 突变在液体活检中更常见，而 KRAS 改变主要在肿瘤中发现。肿瘤 DNA 中检测到的所有 IDH1 突变也在液体活检中得到鉴定。这些发现为一大群 BTC 患者的肿瘤和液体活检基因组景观之间的一致性提供了新的见解，并强调了两种分析在指导治疗处方时的互补性。