摘要

PURPOSE:Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.
EXPERIMENTAL DESIGN:Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.
RESULTS:Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond (P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively).
CONCLUSIONS:We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.

译文

目的: Merkel 细胞癌 (MCC) 是一种罕见的侵袭性皮肤恶性肿瘤,已证明对免疫检查点抑制剂治疗敏感。在这里,我们对 MCC 进行了迄今为止最大的基因组学研究,以表征分子景观,并评估与免疫检查点抑制剂反应的临床和分子相关性。
实验设计: 对来自 MCC 患者的 317 个肿瘤进行了全面的分子分析,包括致癌突变、肿瘤突变负担 (TMB) 、突变特征的评估, 和默克尔细胞多瘤病毒 (MCPyV)。对于 57 名患者的一个子集,进行了一项回顾性分析,以评估与免疫检查点抑制剂反应和疾病生存的临床和分子相关性。
结果: 基因组分析揭示了 TMB 的双峰分布,有 2 个分子上不同的亚组。94% (n = 110) 的 TMB-high 样本显示出紫外线 (UV) 突变特征。MCPyV 基因组 DNA 序列没有在任何 TMB 高病例 (0/117) 中被鉴定出来,但是在 TMB 低病例中的 63% (110/175) 中被鉴定出来。对于 36 名接受检查点抑制剂治疗的可评估患者,总体反应率为 44%,且反应率与审查时的生存率相关 (100% vs.20%,P <0.001)。TMB 高/紫外线驱动肿瘤的反应率为 50%,TMB 低/MCPyV 阳性肿瘤为 41% (P = 0.63)。反应率与治疗线显著相关: 一线为 75%,二线为 39%,三线以上为 18% (P = 0.0066)。PD-1,但不 PD-L1,表达与免疫治疗反应相关 (阳性和阴性 PD-1 分别为 77% 和 21%,P = 0.00598)。
结论: 我们提供了一个全面的 MCC 基因组景观,并证明了免疫治疗反应的临床基因组关联。

Merkel cell carcinoma

肿瘤 恶性肿瘤 疾病
概述  :  

默克尔细胞癌(MCC)是原发于皮肤的一种侵袭性很高的恶性肿瘤,多数认为由表皮Markel细胞发生。1972年Toker首先描述也称之为小梁状肿瘤,非常罕见,在美国每年新诊断的病例大约为2488例,然而近几年来发病率逐年升高。它的发病率仅为黑色素瘤的三十五分之一,但致死率却是黑色素瘤的3倍多。因MMC肿瘤细胞质内有神经内分泌颗粒出现,也被称作原发于皮肤的神经内分泌癌,主要发生于老年人的头颈部及四肢,具有独特的超微结构改变和免疫组化染色特征。手术切除后,易局部复发,也可远处转移,在皮肤源性的肿瘤

Merkel 

       n. 默克尔(姓氏)

       "If at all, this discussion belongs at the end so I don't find it particularly fitting that we are now once again conducting it in the middle of the crisis, as if it were the answer, " Merkel said. “如果欧元债券是解决办法的话,这场讨论(指是否发行欧元债券)也应该在危机最后阶段无路可走时才进行,所以我认为在危机中间再次进行这个议题不太合适,”默克尔说。

 

Cell   英 /sel/   美 /sɛl/

       n. 细胞;电池;蜂房的巢室;单人小室;vi. 住在牢房或小室中

同根词   cellularity n. 细胞性;多孔性;细胞结构

       One of its purposes is to register for all notifications which occur on that cell, node, or server. 其目的之一就是为该单元、节点或服务器上发生的所有通知进行注册。

 

Carcinoma   英 /,kɑːsɪ'nəʊmə/   美 /,kɑrsɪ'nomə/

       n. [肿瘤] 癌;复数 carcinomas或carcinomata

       You may see 'undifferentiated carcinoma of the oesophagus' in your medical reports if you have this type of oesophageal cancer. 如果你患有这种类型的食管癌,你可能会在你的医学报告中看到“食管癌的未分化”。

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