The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.
The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.
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DOI：
10.1158/0008-5472.can-15-0702
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发表时间：
2015-09-15
期刊：
影响因子：
11.2
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
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作者：
Harms PW;Vats P;Verhaegen ME;Robinson DR;Wu YM;Dhanasekaran SM;Palanisamy N;Siddiqui J;Cao X;Su F;Wang R;Xiao H;Kunju LP;Mehra R;Tomlins SA;Fullen DR;Bichakjian CK;Johnson TM;Dlugosz AA;Chinnaiyan AM
默克尔细胞癌（MCC）是一种罕见但高度侵袭性的皮肤神经内分泌肿瘤。默克尔细胞多瘤病毒（MCPyV）可能通过突变的病毒T抗原抑制肿瘤抑制因子（如视网膜母细胞瘤（RB 1））而促进肿瘤发生，但MCPyV阴性MCC的分子发病机制在很大程度上尚未探索。通过我们的MI-ONCOSEQ精确肿瘤学研究，我们对两例MCPyV阴性MCC以及另外14例MCC病例的验证队列（n=16）进行了整合测序。除了先前在TP 53、RB 1和PIK 3CA中鉴定的突变之外，我们还在MCPyV阴性MCC中发现了包括HRAS在内的癌基因的激活突变以及PRUNE 2和NOTCH家族基因的功能丧失突变。MCP γ V阴性肿瘤也显示出高的总体突变负荷（每Mb 10.09 +/-2.32个突变），其特征在于突出的UV特征模式，其中C > T转换包含85%的突变。相比之下，MCPyV阳性肿瘤的突变负荷较低（每Mb 0.40 +/-0.09个突变），并且缺乏UV特征。这些发现表明MCC中存在潜在的本体二分法，其特征在于病毒依赖性或UV依赖性致瘤途径。
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T-antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n=16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 +/− 2.32 mutations per Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 +/− 0.09 mutations per Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.