Unraveling the influence of genetic subtype on spatial configurations of tissue and immune compartment composition in clear cell renal cell carcinoma

摘要 透明细胞肾细胞癌（ccRCC）是一种高度血管化和免疫浸润的癌症， 并且是导致大多数肾癌死亡的原因。值得注意的是，ccRCC是 定义为明确的突变事件，从VHL丢失开始，然后是表观遗传学的丢失。 调节子（例如BAP 1、PBRM 1）位于染色体3 p上。虽然临床研究表明BAP 1 与PBRM 1驱动的病例相比，目前组织学上， 等级是区分这些亚型的唯一特征。此外，研究基因的尝试 肾细胞癌的表达特征仅限于肿瘤细胞， 免疫区室在疾病进展中的确切作用尚未表征，特别是在 与基因驱动子类型的关系。在这里，我提出了一套互补的方法， 检查ccRCC组织中遗传亚型和表型之间的关系， 分子水平。在目标1中，我将开发一个模型来创建 ccRCC载玻片图像，以识别组织的潜在空间配置及其变化方式 在BAP 1和PBRM 1驱动的肿瘤中。在目标2中，我将重点介绍免疫区室- 肿瘤的浸润和边界免疫群体，并将识别基因的模式 与免疫治疗的内在和获得性抗性相关的表达。这项工作 站在提供驱动遗传事件和基础之间的关系清晰 肾细胞癌生物学，因此有可能立即影响临床 决策。

Abstract Clear cell renal cell carcinoma (ccRCC) is a highly vascularized and immune infiltrated cancer, and is responsible for the majority of deaths caused by kidney cancer. Notably, ccRCC is defined by clear mutational events, starting with VHL loss, and followed by loss of an epigenetic regulator (e.g. BAP1, PBRM1) on chromosome 3p. While clinical studies have associated BAP1 driven tumors with worse prognosis relative to PBRM1 driven cases, at present histological grade is the only feature distinguishing these subtypes. Moreover, attempts to study the gene expression characteristics of renal cell carcinoma have been limited to tumor cells, leaving the precise role of the immune compartment in disease progression uncharacterized, especially in relation to genetic driver subtype. Here, I present a set of complementary approaches to examine the relationship between genetic subtype and phenotype in ccRCC at the tissue and molecular levels. In Aim 1, I will develop a model to create condensed representations of ccRCC slide images to identify underlying spatial configurations of tissue, and how they vary across BAP1 and PBRM1 driven tumors. In Aim 2, I will focus on the immune compartment — the infiltrating and bordering immune populations of the tumor, and will identify patterns of gene expression associated with both intrinsic and acquired resistance to immunotherapy. This work stands to provide clarity on the relationship between driving genetic events and fundamental renal cell carcinoma biology, and consequently has the potential to immediately impact clinical decision making.