Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations
Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations
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DOI：
10.1634/theoncologist.2015-0241
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发表时间：
2016-01-01
期刊：
影响因子：
5.8
通讯作者：
Miller, Vincent A.
中科院分区：
文献类型：
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作者：
Ali, Siraj M.;Pal, Sumanta K.;Miller, Vincent A.
背景。晚期阴茎鳞状细胞癌（PSCC）由于疾病的侵袭性和缺乏有效的全身治疗而与较差的生存率相关。采用综合基因组分析（CGP）来鉴定临床相关的基因组改变（CRGAs）。材料与方法。从晚期PSCC患者40 pm的福尔马林固定石蜡包埋切片中提取DNA。CGP对捕获的基于接头连接的文库进行杂交，平均覆盖深度为697 X，涵盖736个癌症相关基因的3,769个外显子以及来自19个癌症中经常重排的基因的47个内含子。CRGAs被定义为与市场上的靶向治疗相关的基因组改变（GAs），或正在机制驱动的临床试验中进行评估。对20例中位年龄为60岁（46-87岁）的男性患者进行了评估。17例（85%）为IV期，3例（15%）为III期。CGP共发现109个GAs（每个肿瘤5.45个），其中44个为CRGAs（每个肿瘤7.7个）。19例（95%）患者中检出至少一种CRGA，其中最常见的CRGA为CDKN2A点突变和纯合缺失（40%）、NOTCH1点突变和重排（25%）、P1K3CA点突变和扩增（25%）、EGFR扩增（20%）、CCND1扩增（20%）、BRCA2插入/缺失（10%）、R1CTOR扩增（10%）和FBXW7点突变（10%）。CGP在晚期PSCC患者中发现了CRGAs，包括EGFR扩增和P1K3CA改变，这可以导致这些患者合理给予靶向治疗并随后获益。
Background. Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs).Materials and Methods. DNA was extracted from 40 p.m of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization captured, adaptor ligation-based libraries to a mean coverage depth of 697 X for 3,769 exons of 736 cancer related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials.Results. Twenty male patients with a median age of 60 years (range, 46-87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (7.7 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), P1K3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), R1CTOR amplifications (10%), and FBXW7 point mutations (10%).Conclusion. CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and P1K3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients.