Background/Objectives: Immune checkpoint inhibitors (ICIs) are frontline treatment for advanced Merkel Cell Carcinoma (MCC), regardless of viral status. Frontline ICIs provide durable benefit to only half of patients, highlighting a need for alternative therapies. In this study, the objective is to leverage whole exome sequencing (WES) and transcriptome sequencing (WTS) to distinguish genomic alterations associated with ICI response. Investigate differential genomic alterations between virus-positive (VP) and virus-negative (VN)-MCC to identify novel therapeutic targets. Methods: A total of 95 MCC cases underwent WES and WTS. Utilizing computational pipelines applied to WES, we identified viral status and tumor mutational burden (TMB). RNA-seq data was used to characterize the immune microenvironment. Results: Of 95 MCC cases, 57 (60%) were VP-MCC and 38 (40%) were VN-MCC. Median TMB was higher in VN-MCC (27.5 vs. 1 Muts/Mb). Mutations inTP53,RB1,NOTCH1,KMTD2,KMT2C, andPIK3CAwere primarily found in VN-MCC. MAPK Pathway Activity Score, NK cell infiltration, and the immune checkpoint geneCD276in VN-MCC tumors were upregulated. No overall survival (OS) difference was identified between VP and VN-MCC, even after ICIs. Conclusions: MCC oncogenesis and treatment response transcend viral status. While mutational analysis confirms previous findings, assessment of the transcriptome and tumor microenvironment suggests alternate therapeutic targets.
背景/目的：无论病毒状态如何，免疫检查点抑制剂（ICI）是晚期默克尔细胞癌（MCC）的一线治疗方法。一线ICI仅对半数患者产生持久获益，凸显了对替代疗法的需求。本研究旨在利用全外显子组测序（WES）和转录组测序（WTS）来区分与ICI应答相关的基因组改变，并探究病毒阳性（VP）与病毒阴性（VN）-MCC之间的差异基因组改变，以识别新的治疗靶点。方法：对95例MCC病例进行了WES和WTS分析。通过应用于WES的计算流程，我们确定了病毒状态和肿瘤突变负荷（TMB）。利用RNA-seq数据来表征免疫微环境。结果：在95例MCC病例中，57例（60%）为VP-MCC，38例（40%）为VN-MCC。VN-MCC的中位TMB更高（27.5 vs. 1 Muts/Mb）。TP53、RB1、NOTCH1、KMTD2、KMT2C和PIK3CA的突变主要存在于VN-MCC中。VN-MCC肿瘤中的MAPK通路活性评分、NK细胞浸润以及免疫检查点基因CD276表达上调。即使在接受ICI治疗后，VP-MCC与VN-MCC之间的总生存期（OS）也无差异。结论：MCC的肿瘤发生和治疗应答超越了病毒状态。虽然突变分析证实了既往发现，但对转录组和肿瘤微环境的评估提示了替代治疗靶点。
Molecular Characterization of Polyomavirus-Positive and Negative Merkel Cell Carcinoma
肿瘤(癌症)患者之家