全外显子组测序在阴茎鳞状细胞癌中揭示了与头颈部鳞状细胞癌相似的新型预后分类和药物靶点。
Whole-exome Sequencing in Penile Squamous Cell Carcinoma Uncovers Novel Prognostic Categorization and Drug Targets Similar to Head and Neck Squamous Cell Carcinoma.
机构信息
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
The University of Texas MD Anderson Cancer Center, Houston, Texas.
出版信息
Clin Cancer Res. 2021 May 1;27(9):2560-2570. doi: 10.1158/1078-0432.CCR-20-4004. Epub 2021 Jan 13.
PURPOSE
Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets.
EXPERIMENTAL DESIGN
PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC-enriched mutational patterns based on their association with the Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies.
RESULTS
We identified that most PSCC samples showed enrichment for Notch pathway ( = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased tumor mutation burden (TMB; CC, 0.71; < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13-92.9); = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC-enriched subset [HR, 2.41 (1.11-6.77); = 0.042].
CONCLUSIONS
This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications..
目的
阴茎鳞状细胞癌（PSCC）较为罕见，治疗选择有限。我们报告首例全外显子组测序（WES）分析，并比较 PSCC 与其他鳞状细胞癌（SCC）的分子谱，旨在确定常见的新靶点。
实验设计
对 34 例前瞻性随访患者的 PSCC 和匹配的正常阴茎组织进行基因组 WES 和人乳头瘤病毒检测。我们通过两种方法进行肿瘤突变特征估计，首先是鉴定 APOBEC 相关的突变富集，其次是根据与癌症体细胞突变目录中的突变特征的相关性对 PSCC 富集的突变模式进行分类。我们对我们的 PSCC 队列和 TCGA 研究中的其他 SCC 进行了广泛的基因组比较。
结果
我们发现大多数 PSCC 样本显示 Notch 通路改变富集（=24，70.6%），与头颈部鳞状细胞癌（HNSC）相当。PSCC 的突变特征与 HNSC 特征最相似。PSCC 样本显示两种不同的突变特征富集，第一种与 AID/APOBEC 的致癌活性相关，第二种与 DNA 错配修复缺陷和微卫星不稳定相关。MP1 富集与肿瘤突变负荷（TMB；CC，0.71；<0.0001）增加呈正相关，与 MP2 亚组相比，与生存率显著降低相关[HR，10.2（1.13-92.9）；=0.039]。我们表明，PSCC 的亚组（38%）存在 APOBEC 相关突变特征富集，与非 APOBEC 富集亚组相比，TMB 显著更高，总生存率更差[HR，2.41（1.11-6.77）；=0.042]。
结论
本研究鉴定了 PSCC 和 HNSC 之间的新型可药物靶点和突变特征相似性，具有潜在的临床意义。
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