Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic allterations and targets of therapy
Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic allterations and targets of therapy
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DOI：
10.1038/modpathol.2013.135
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发表时间：
2014-02-01
期刊：
影响因子：
7.5
通讯作者：
Stephens, Philip J.
中科院分区：
文献类型：
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作者：
Ross, Jeffrey S.;Wang, Kai;Stephens, Philip J.
尽管膀胱尿路上皮癌（UC）通常预示着良好的预后，但转移性肿瘤通常会出现侵袭性的临床病程。从 35 个 IV 期 UC 的 40 μm 福尔马林固定石蜡包埋 (FFPE) 切片中提取 DNA，这些 UC 在初次手术和常规化疗后复发并进展。对杂交捕获的基于接头连接的文库进行了下一代测序 (NGS)，该文库包含 182 个癌症相关基因的 3320 个外显子以及来自癌症中经常重排的 14 个基因的 37 个内含子，平均测序深度为 1164 倍，并评估所有类别的基因组改变 (GA)。可操作的 GA 被定义为影响市场上或注册临床试验中靶向抗癌疗法选择的 GA。总共鉴定了 139 个 GA，每个肿瘤平均有 4.0 个 GA（范围 0-10），其中 78 个（56%）被认为是可操作的，每个肿瘤平均有 2.2 个 GA（范围 0-7）。二十九 (83%) 病例至少含有一种可采取行动的 GA，包括： PIK3CA（9 例；26%）； CDKN2A/B（8例；23%）； CCND1（5 例；14%）； FGFR1（5 例；14%）； CCND3（4 例；11%）； FGFR3（4 例；11%）； MCL1（4例；11%）； MDM2（4例；11%）； EGFR（2例，6%）； ERBB2（HER2/neu）（2例，6%）； NF1（2 例，6%）和 TSC1（2 例，6%）。值得注意的其他改变包括 TP53（19 例，54%）和 RB1（6 例；17%）。在近一半的病例中，参与染色质修饰的基因通过无义突变、剪接位点突变或移码插入缺失以相互排斥的方式发生改变，包括 KDM6A（10 例；29%）和 ARID1A（7 例；20%）。对膀胱 35 个 UC 进行的综合 NGS 揭示了 83% 的病例中多种可操作的 GA，这有可能为复发和转移性疾病患者的治疗决策提供信息。
Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 mu m of formalin-fixed, paraffin-embedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 x and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0-10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0-7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.