Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations

利用病毒扰动鉴定新型致癌信号通路

• 批准号: 10460971
• 负责人: James A. DeCaprio
• 金额: $ 101.45万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460971
• 关键词: Basal cell carcinoma; Cause of Death; Cells; Child; Chromatin; Complex; Disease; Etiology; Gene Amplification; Gene Expression; Genome; Incidence; Large T Antigen; Learning; Lysine; MYCL1 gene; Malignant Epithelial Cell; Malignant Neoplasms; Merkel cell carcinoma; Methodology; Mutation; Oncogenic; Pathway interactions; Pattern; Phenotype; RB1 gene; Signal Pathway; Skin Cancer; Small T Antigen; Squamous cell carcinoma; Sun Exposure; TP53 gene; Time; Transferase; Tumor Suppressor Genes; UV induced; Viral; Virus; cancer type; immune checkpoint blockade; insight; melanoma; mortality; novel; posters; programs; recruit; success; tool; tumor; tumorigenesis; ultraviolet; viral DNA

Project Summary Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin; a highly aggressive cancer with a 40% 2-year mortality rate. While the incidence of MCC is 25-fold less frequent than melanoma, it is 13-fold more likely to cause death. In a remarkably short time, MCC has gone from an unknown cancer to the poster child for the success of checkpoint blockade therapy (CBT). With the application of powerful new tools to the study of MCC, it can be expected that the next 7 years will continue to bring remarkable new discoveries with the potential to increase our insight not only into this cancer but into many other cancers as well. There are two forms of MCC with different etiologies but nearly identical presentations. Virus-negative (VN) MCC is caused by excessive sunlight exposure resulting in ultraviolet (UV) induced damage to the genome, a pattern typical for other skin cancers including melanoma, squamous cell carcinoma and basal cell carcinoma. In contrast, virus-positive (VP) MCC is caused by integration of the MCPyV viral DNA into the host cell genome with expression of a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). Despite the near identical phenotypes, VN-MCC and VP-MCC have striking differences in their overall genome mutation rate. The VN-MCC has a much higher tumor mutational burden (TMB, median ~ 40 mutations/mB) than VP-MCC (median 2/mB). VN-MCC has near universal inactivation of the RB1 and TP53 tumor suppressor genes as well as in the lysine methyl transferase genes KMT2C and KMT2D (also known as MLL3 and MLL4). In addition, VN-MCC frequently contains amplification of MYCL or MYC. In contrast, VP- MCC can be recognized by the presence of integrated MCPyV genomes, the absence of UV mutation signature, a low TMB, and few if any mutations. Instead, VP-MCC expresses MCPyV LT that functionally inactivates RB while ST recruits MYCL to the EP400 chromatin modifying complex to induce profound changes in gene expressions. These distinctions between VP-MCC and VN-MCC raises the question of what we can learn about each form of MCC that can inform us about the other. We propose that the distinct mechanisms of oncogenesis in VN-MCC and VP-MCC provides us with the unique opportunity to use orthogonal methodologies to gain a clearer insight into MCC. We propose that expression of MCPyV LT and ST is capable of inducing the relevant phenotypic changes observed in VP-MCC that occur through the inactivating mutations of RB1, TP53, and KMT2C/D genes and amplification of MYCL in VN-MCC. Our cancer program has made remarkable progress in distinguishing between VN-MCC and VP-MCC and is now poised to exploit this opportunity to leverage insights gained from each type of MCC to inform the other that will lead to significant insights into this disease. Furthermore, we expect that these insights will provide useful insights into the oncogenic pathways that contribute to other cancer types.

项目摘要 默克尔细胞癌（MCC）是皮肤的主要神经内分泌癌。高度侵略性 癌症为40％2年死亡率。虽然MCC的发生率比黑色素瘤少25倍，但 造成死亡的可能性要高13倍。在很短的时间内，MCC已从未知的癌症变成 Seckpoint Blockade治疗（CBT）成功的海报儿童。随着功能强大的新型 研究MCC的工具，可以预料，未来7年将继续带来非凡的新事物 发现不仅有可能增加对这种癌症的见解，而且有可能增加许多其他癌症的发现 出色地。有两种形式的MCC具有不同的病因，但几乎相同。病毒阴性 （VN）MCC是由过度阳光暴露引起的，导致紫外线（UV）诱发的损害 基因组，一种典型的其他皮肤癌的模式，包括黑色素瘤，鳞状细胞癌和基底细胞 癌。相反，病毒阳性（VP）MCC是由MCPYV病毒DNA整合到宿主中引起的 细胞基因组具有大型T抗原（LT）和完整的小抗原（ST）的截短形式的表达。 尽管表型几乎相同，但VN-MCC和VP-MCC的总体差异很大 基因组突变率。 VN-MCC具有更高的肿瘤突变负担（TMB，中位数〜40 突变/MB）比VP-MCC（中值2/MB）。 VN-MCC几乎对RB1和TP53的普遍失活 肿瘤抑制基因以及赖氨酸甲基转移酶基因KMT2C和KMT2D（也称为 mll3和mll4）。此外，VN-MCC经常包含MYCL或MYC的放大。相反，VP- MCC可以通过综合的MCPYV基因组的存在来识别，不存在紫外线突变 签名，低TMB，几乎没有突变。相反，VP-MCC表示功能上的MCPYV LT 灭活RB，而St将MYCL招募到EP400染色质修饰复合物以引起深刻的变化 在基因表达中。 VP-MCC和VN-MCC之间的这些区别提出了我们可以学到什么的问题 MCC的形式可以告知我们对方。我们提出了肿瘤发生的不同机制 VN-MCC和VP-MCC为我们提供了使用正交方法来获得的独特机会 对MCC的了解更清晰。我们建议MCPYV LT和ST的表达能够诱导相关 通过RB1，TP53和 kmt2c/d基因和VN-MCC中MyCl的扩增。我们的癌症计划取得了显着进步 在区分VN-MCC和VP-MCC时，现在有望利用这一机会来利用 从每种类型的MCC中获得的见解，以告知对方，这将导致对这种疾病的重大见解。 此外，我们期望这些见解将为致癌途径提供有用的见解 有助于其他癌症类型。