Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies
Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies
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DOI：
10.1002/cncr.29738
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发表时间：
2016-01-15
期刊：
影响因子：
6.2
通讯作者：
Ross, Jeffrey S.
中科院分区：
文献类型：
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作者：
Al-Rohil, Rami N.;Tarasen, Ashley J.;Ross, Jeffrey S.
作者假设，全面的基因组分析的晚期皮肤鳞状细胞癌（cSCC）可以识别基因组衍生的药物治疗靶点的患者与常规therapy-resistant disease.METHODSComprehensive基因组分析的315个癌症基因被施加到50纳克的DNA从122 cSCC的情况下，所有类别的基因组变异（GA）的评估。临床相关的基因组改变（CRGA）被定义为在市场上或在注册的临床试验中鉴定抗癌药物的那些。有21名女性（17%）和101名男性（83%），中位年龄为64.9岁（范围，21-87岁）。11例cSCC病例（9%）为组织学AJCC 1级，69例（57%）为2级，42例（34%）为3级。77例（63%）原发性cSCC用于测序。37%的病例中转移性病变进行了测序。总共鉴定了1120个GA（每个肿瘤平均9.2个GA），100%的病例至少有1个变异。在122例cSCC中，107例（88%）至少有1例CRGA（每个cSCC有2.5个CRGA），包括NOTCH 1（43%）; patched 1（PTCH 1）（11%）; BRCA 2（10%）; HRAS（8%）;共济失调毛细血管扩张突变（ATM）（7%）; erb-B2受体酪氨酸激酶4（ERBB 4）（7%）;神经纤维瘤病1型（NF 1）（7%）; erb-B2受体酪氨酸激酶2（ERBB 2）（6%）;磷脂酰肌醇-4，5-二磷酸3-激酶，催化亚单位α（PIK 3CA）（6%）;细胞周期蛋白D1（CCND 1）（6%）;表皮生长因子受体（EGFR）（5%）; E3泛素蛋白连接酶（FBXW 7）（5%）。发现大约88%的cSCC患者具有临床相关的GA，其具有指导用靶向治疗剂治疗晚期肿瘤患者的潜力。Cancer 2016;122：249-257. (c)2015年美国癌症协会。目前的研究突出了122例复发性和难治性皮肤鳞状细胞癌的突变景观，并专注于发现有可能指导晚期和转移性疾病患者靶向治疗选择的基因组靶点。在本文报道的122例患者中，88%的患者的综合基因组分析似乎与能够指导治疗决策的临床相关基因组改变的检测相关。
BACKGROUNDThe authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic-derived drug targets of therapy for patients with conventional therapy-resistant disease.METHODSComprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials.RESULTSThere were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%).CONCLUSIONSIn the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249-257. (c) 2015 American Cancer Society.The current study highlights the mutational landscape in 122 cases of recurrent and refractory cutaneous squamous cell carcinoma and is focused on the discovery of genomic targets that have the potential to guide targeted therapy selection for patients with advanced and metastatic disease. In 88% of the 122 patients reported herein, comprehensive genomic profiling appears to be associated with the detection of clinically relevant genomic alterations capable of guiding therapeutic decisions.