Impact of cancer predisposition on oncogenic process, microenvironment, and treatment

癌症易感性对致癌过程、微环境和治疗的影响

• 批准号: 10367242
• 负责人: FENG CHEN
• 金额: $ 48.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367242
• 关键词: BRCA1 gene; Oncogenic; Process; brca gene; cancer predisposition

Our previous study of more than 10 thousand tumors across 33 cancer types identified over 800 germline predisposition variants in both tumor suppressors and oncogenes. Although the impact of some of these variants on cancer onset, incidence rate, and clonality have been documented, the effects of these variants (especially when compared to somatic mutations) on molecular characteristics of cancer cells, contributions of non-cancer cells having germline variants, and treatment responses, are far less studied. Our recent single cell(sc) /single nucleus(sn) RNA-seq analyses of cancer samples provided comprehensive expression profiles at a single cell resolution and revealed the expression of key cancer predisposition genes, such as BRCA 112, VHL, BAP1, and c-MET in many non-cancer stromal and immune cells in the tumor microenvironment (TME). Our pilot analyses also revealed significant differential gene expression in cancer and non-cancer cells based on the nature of the driver event being germline or somatic. We hypothesize that tumors with certain germline predisposition variants in tumor suppressors and oncogenes may show differences in tumor progression and treatment responses from those tumors with somatic mutations in the same genes due to differential influence on mutational, transcriptomic, and proteomic profiles of the cancer cells and potentially distinctive contributions from non-cancer cells having those germline changes. To take advantage of the considerable progress over the last few years, namely newly accumulated cancer sequencing data, advances in single cell omics, patient-derived xenografts (PDX), and tumor genetic models, we propose to test these hypotheses by performing the following: compare germline predisposition variants and somatic mutations to dissect their differential biological impacts and interactions using computational analysis (Aim 1); perform single nucleus RNA-seq/ATAC-seq, spatial transcriptomics, and multiplex imaging analysis of human cancer samples to reveal the differential roles of germline predisposition variants and somatic mutations in tumor cells and the TME (Aim 2); use PDX and genetic cancer models to investigate potential functional differences between germline predisposition variants and somatic mutations in tumor cells, TME, and treatment responses (Aim 3). Results from this study will advance our understanding of the unique contributions of germline variants to cancer cells and TME alike, improve genetic counseling and prognosis, and provide guidance for differential treatment of tumors carrying germline variants vs somatic mutations in key cancer driver genes.

我们之前对33种癌症类型的1万多个肿瘤的研究确定了800多个生殖系 肿瘤抑制基因和癌基因的易感性变异。虽然其中一些影响 已经记录了癌症发病、发病率和克隆性的变异，这些变异的影响 （特别是当与体细胞突变相比时）对癌细胞分子特征的影响， 对具有生殖系变异体的非癌细胞和治疗反应的研究少得多。我们最近的单曲 癌症样品的细胞（sc）/单核（sn）RNA-seq分析提供了全面的表达谱 在单细胞分辨率下，揭示了关键癌症易感基因的表达，如BRCA 112， VHL、BAP 1和c-MET在肿瘤微环境（TME）中的许多非癌基质细胞和免疫细胞中。 我们的初步分析还揭示了癌症和非癌细胞中基于基因表达的显着差异。 驾驶员事件的性质是生殖系还是体细胞。我们假设具有特定生殖系的肿瘤 肿瘤抑制基因和癌基因中的易感性变体可能在肿瘤进展中显示出差异， 来自那些由于差异性免疫缺陷而在相同基因中具有体细胞突变的肿瘤的治疗反应， 对癌细胞的突变、转录组和蛋白质组谱的影响， 来自具有这些生殖系变化的非癌细胞的贡献。为了充分利用 过去几年的进展，即新积累的癌症测序数据，单细胞测序的进展， 组学、患者来源的异种移植物（PDX）和肿瘤遗传模型，我们建议通过以下方法来检验这些假设： 进行以下操作：比较生殖系易感性变体和体细胞突变，以剖析它们的 使用计算分析的不同生物影响和相互作用（目标1）;执行单一 核RNA-seq/ATAC-seq、空间转录组学和人类癌症的多重成像分析 样本，以揭示生殖系易感性变异和体细胞突变在肿瘤中的不同作用 细胞和TME（Aim 2）;使用PDX和遗传癌症模型研究潜在的功能 肿瘤细胞中生殖系易感性变体和体细胞突变之间的差异，TME，以及 治疗反应（目标3）。这项研究的结果将促进我们对独特的 生殖系变异对癌细胞和TME的贡献，改善遗传咨询和预后， 并为携带生殖系变异与体细胞突变的肿瘤的差异治疗提供指导， 癌症驱动基因