New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next‐Generation Sequencing. (21st February 2014)

• Record Type: Journal Article
• Authors: Ross, Jeffrey S.; Wang, Kai; Gay, Laurie; Al‐Rohil, Rami; Rand, Janne V.; Jones, David M.; Lee, Hwa J.; Sheehan, Christine E.; Otto, Geoff A.; Palmer, Gary; Yelensky, Roman; Lipson, Doron; Morosini, Deborah; Hawryluk, Matthew; Catenacci, Daniel V. T.; Miller, Vincent A.; Churi, Chaitanya; Ali, Siraj; Stephens, Philip J.
• Is Part Of: Oncologist. Volume 19:Number 3(2014)
• Page Start: 235
• Page End: 242
• Publication Date: 2014-02-21
• Subjects: Intrahepatic cholangiocarcinoma -- Next‐generation sequencing -- Driver mutations -- Targeted therapy; Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2013-0352
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. Methods: DNA sequencing of hybridization‐captured libraries was performed for 3, 320 exons of 182 cancer‐related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 μm of 28 formalin‐fixed paraffin‐embedded ICC specimens and sequenced to high coverage. Results: The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 ( FGFR2 ‐ KIAA1598, FGFR2‐BICC1, FGFR2‐TACC3, and RABGAP1L ‐ NTRK1 ). Conclusion: Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients. Abstract : In this study, the authors hypothesized that genomic profiling of clinical intrahepatic cholangiocarcinoma samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. Two‐thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for individual patients. Abstract : 摘要 摘要 . 肝内胆管癌 (intrahepatic cholangiocarcinoma, ICC) 是原发性肝癌的一种亚型，很少可以通过手术治愈，且其发病率在日益增高。复发性肝内胆管癌预后不佳，而目前的非靶向全身疗法通常是从其他胃肠道恶性肿瘤的治疗推演而来。我们提出假设：临床ICC 样本的基因组学特征分析将鉴别与靶向疗法有关的基因组学变化，而且可能有助于制定个体化疗法。 方法 . 对 182 个癌症相关基因的 3, 320 个外显子以及癌症中频繁重排的 14 个基因的 36 个内含子进行杂交捕获DNA 文库测序。从 28 个 40 μm 厚福尔马林固定、石蜡包埋的 ICC 标本分离出 DNA 样本，并测序到高覆盖率水准。 结果 . 最常见的 DNA 变化可见于 ARID1A (36%)、 IDH1/2 (36%) 、 TP53 (36%) 以及扩增的 MCL1 (21%)。从至少有一个潜在活性变化的基因中采集了二十例 (71%) 测序结果，这些基因包括 FGFR2 (14%)、 KRAS (11%)、 PTEN (11%)、 CDKN2A (7%)、 CDK6 (7%)、 ERBB3 (7%)、 MET (7%)、 NRAS (7%)、 BRCA1 (4%)、 BRCA2 (4%)、 NF1 (4%)、 PIK3CA (4%)、 PTCH1 (4%) 以及 TSC1 (4%)。四例 (14%) ICC病例表现出新基因融合的特征，涉及酪氨酸激酶 FGFR2 和 NTRK1（ FGFR2‐KIAA1598 、 FGFR2‐ BICC1 、 FGFR2‐TACC3 及 RABGAP1L‐NTRK1 ）。 结论 . 从本研究中三分之二患者采集到的基因组变化与靶向疗法相关，并有可能对患者个体化疗法有帮助。 The Oncologist 2014;19:235–242