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

揭示遗传亚型对透明细胞肾细胞癌组织和免疫区室组成空间配置的影响

基本信息

批准号：
10439647
负责人：
Jackson Nyman
金额：
$ 2.68万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-03-31
项目状态：
已结题

项目摘要

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.

抽象的透明细胞肾细胞癌（ccRCC）是一种高度血管化和免疫浸润的癌症，肾癌造成的大部分死亡都是由它造成的。值得注意的是，ccRCC 是由明确的突变事件定义，从 VHL 丢失开始，然后是表观遗传丢失染色体 3p 上的调节因子（例如 BAP1、PBRM1）。虽然临床研究表明 BAP1 相对于PBRM1驱动的病例，驱动的肿瘤预后更差，目前的组织学等级是区分这些亚型的唯一特征。此外，还尝试研究该基因肾细胞癌的表达特征仅限于肿瘤细胞，因此免疫区室在疾病进展中的精确作用尚未表征，特别是在与遗传驱动亚型的关系。在这里，我提出了一套补充方法检查组织中 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以下内容的压缩表示： ccRCC 幻灯片图像可识别组织的潜在空间配置及其变化方式跨 BAP1 和 PBRM1 驱动的肿瘤。在目标 2 中，我将重点关注免疫区室 — 肿瘤的浸润和边界免疫群体，并将识别基因模式表达与免疫治疗的内在和获得性耐药相关。这部作品旨在阐明驱动遗传事件和基本原理之间的关系肾细胞癌生物学，因此有可能立即影响临床决策。