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

摘要 肾透明细胞癌(CcRCC)是一种高度血管化和免疫浸润性癌症， 并对肾癌造成的大部分死亡负有责任。值得注意的是，ccRCC是 由明确的突变事件定义，以VHL缺失开始，随后是表观遗传学缺失 染色体3p上的调节基因(如BAP1、PBRM1)。虽然临床研究发现BAP1与 与PBRM1驱动的病例相比，目前组织学上预后较差的驱动肿瘤 等级是区分这些子类型的唯一特征。此外，试图研究这种基因 肾细胞癌的表达特征仅限于肿瘤细胞，留下了 免疫间隔在疾病进展中的确切作用尚未确定，尤其是在 与遗传驱动亚型的关系。在这里，我介绍了一组补充方法，以 在组织和组织中检查CcRCC的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幻灯片图像，以确定组织的基本空间构型及其变化方式 跨BAP1和PBRM1驱动的肿瘤。在《目标2》中，我将重点放在免疫舱- 肿瘤的浸润性和交界性免疫群体，并将确定基因的模式 表达与免疫治疗的内在和获得性耐药有关。这部作品 旨在澄清驱动基因事件和基本因素之间的关系 肾细胞癌生物学，因此有可能立即影响临床 做决定。

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.