Smith Joshua D, Bhangale Apurva D, Gu Wenjin, Brummel Collin, Gensterblum-Miller Elizabeth, McLean Scott, Harms Paul W, Harms Kelly L, Bichakjian Christopher K, Spector Matthew E, Mills Ryan E, Brenner J Chad
UPMC Health System, United States.
University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
Mol Cancer Res. 2025 Jul 21. doi: 10.1158/1541-7786.MCR-24-1138.
Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end-users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV-positive), 11 (20.4 %) of which had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5 %), FAT1 (n = 9, 16.7 %), KMT2D (n = 9, 16.7 %), and RB1 (n = 7, 13.0 %). In 36 of 44 (81.8 %) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into COSMIC Tier 1 or Tier 2 cancer-related human genes. Implications: A combined genomics score incorporating tumor mutational burden and copy number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status, thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.
默克尔细胞癌（MCC）是一种侵袭性疾病，生存预后较差且发病率不断上升。目前迫切需要加强对肿瘤发生细胞机制的理解，验证预测侵袭性疾病的可靠基因特征，并开发新型信息学工具以简化对默克尔细胞多瘤病毒（MCPyV）-宿主基因组相互作用的分析。从54例MCC肿瘤中提取基因组DNA，用于外显子测序和对一个226基因panel进行深入的基因分析。我们进一步开发了一个强大的信息学软件包（MCPyViewer），该软件包针对MCPyV整合位点分析进行了优化，并具有图形输出功能，以简化终端用户的使用。最后，我们评估了特定基因特征对我们队列中MCC特异性生存的预后影响。我们的研究纳入了54例患者（n = 44例MCPyV阳性），其中11例（20.4%）在最后一次随访时死于MCC。高频改变的人类基因包括LRP1B（n = 10，18.5%）、FAT1（n = 9，16.7%）、KMT2D（n = 9，16.7%）和RB1（n = 7，13.0%）。在44例（81.8%）MCPyV阳性肿瘤中的36例中，我们确定病毒整合到人类基因组中，每个肿瘤的整合事件中位数为2次。在6个肿瘤中，MCPyV整合到COSMIC一级或二级癌症相关人类基因中。意义：结合肿瘤突变负荷和拷贝数变异的综合基因组评分对控制淋巴结转移和肿瘤MCPyV状态的MCC特异性生存具有很强的预后价值，因此，我们的研究为MCC的预后标志物和肿瘤发生机制增添了关键的理解。
