Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
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DOI：
10.18632/oncotarget.6494
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Choi J
中科院分区：
文献类型：
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作者：
Goh G;Walradt T;Markarov V;Blom A;Riaz N;Doumani R;Stafstrom K;Moshiri A;Yelistratova L;Levinsohn J;Chan TA;Nghiem P;Lifton RP;Choi J
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癌，80%的病例与默克尔细胞多瘤病毒（MCPyV）相关。为了确定MCC的遗传基础，我们对49个MCC进行了外显子组测序。我们发现，MCP γ V阴性MCC具有高突变负荷（中位数为1121个体细胞单核苷酸变体（SSNV），每个外显子组中有RB 1和TP 53的频繁突变，以及染色质修饰（ASXL 1，MLL 2和MLL 3），JNK（MAP 3 K1和TRAF 7）和DNA损伤途径（ATM，MSH 2和BRCA 1）中基因的其他损伤性突变。相比之下，MCPyV阳性MCC携带很少的SSNV（中位数为12.5个SSNV/肿瘤），在上述基因中没有SSNV。在这两个亚组中，预计存在罕见的促癌突变，可激活PI 3 K途径（HRAS、KRAS、PIK 3CA、PTEN和TSC 1）并灭活Notch途径（Notch 1和Notch 2）。TP 53突变在病毒阴性MCC中似乎具有临床相关性，因为这些肿瘤中有37%在TP 53的p.R248和p.P278处具有潜在的靶向功能获得性突变。此外，TP 53突变状态预测早期MCC的死亡（TP 53突变型与野生型I期和II期MCC的5年生存率分别为20%和92%; P = 0.0036）。最后，我们鉴定了MCPyV阴性和MCPyV阳性MCC中的肿瘤新抗原。我们发现，病毒阴性MCC比黑色素瘤或非小细胞肺癌携带更多的肿瘤新抗原（中位数分别为173，65和111个新抗原/样本），这两种癌症的免疫检查点阻断可以产生持久的临床反应。总的来说，这些数据支持对病毒阴性MCC使用免疫疗法。
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.