Deciphering Clonal Evolution in Hereditary Renal Cell Carcinomas

1背景：对推动癌症生长和进展的因素有了更好的理解 2改善癌症患者预后的基础。冯·希佩尔-林道(VHL)患者 疾病在一生中会发展成多种血管肿瘤，其中包括数百例恶性肿瘤。 4例囊性肾透明细胞癌(CcRCC)。这些肿瘤是人类基因组的镜像 5例散发性肾小管细胞癌，临床表型多样。分析多个独立的肿瘤 6出现在相同的生殖系和宿主环境中，提供了一种内在受控的模式 7研究癌症发生和发展的一般因素。我们将利用 8个独特的VHL疾病临床队列患者在临床中心研究分子 9景观(目标1)、肿瘤微环境(TME)(目标2)和代谢组 10(目标3)促进或抑制癌症生长。 11种方法：受试者将从泌尿外科肿瘤学招募到这项前瞻性队列研究中 12分部在国家癌症研究所。将跟踪单个肿瘤的生长动力学 13放射学上。在采购过程中，肿瘤被识别并与成像相关联。我们会 14执行多参数分子图谱，整合所有数据集以实现我们的研究目标。 15使用下一代测序，我们将描述恶性事件的特征 16转化(目标1.1)和与差异生长动力学有关的分子事件 17(目标1.1)。我们将探索与肾外部位肿瘤形成相关的事件。 18(目标1.3)以及分子/环境变异如何影响不同的表型渗透 19在VHL家族中(目标1.4)。为了评估TME的作用，我们将使用基因组图谱来 20评估新抗原图景(目标2.1)，并确定不同免疫细胞谱系 21 RNA测序(目标2.2)。我们将用多重免疫组织化学方法验证这些变化。 22(IHC)方法。我们将使用转录组图谱来评估受干扰的代谢组(目标 23 3.1)，并进行一项初步研究，以稳定同位素评估基因组和转录组的变化 24例术中获得的VHL肿瘤组织的可分辨代谢谱。 结论：这将是VHL中最全面的癌症分子图谱。 26种疾病。它有可能解决关于进化癌症生物学的关键问题，并 27确定肿瘤生长和进展的触发因素，从而确定预测或预后的生物标志物 28这可能与癌症有更广泛的相关性。它可能为治疗癌症提供新的治疗策略。 29遗传性和散发性慢性肾细胞癌的治疗和预防。

1 Background: An improved understanding of the factors that drive cancer growth and progression is 2 fundamental for improving outcomes in patients with cancer. Individuals with Von Hippel-Lindau (VHL) 3 disease develop multiple vascular tumours in their lifetime including many hundreds of malignant 4 cysts and clear cell renal cell carcinoma (ccRCCs). These tumours are the genomic mirror image of 5 sporadic ccRCCs and display variable clinical phenotypes. Profiling multiple, independent tumours 6 that have arisen in an identical germline and host environment offers an intrinsically controlled model 7 to study the factors underlying cancer evolution and progression in general. We will leverage the 8 unique clinical cohort of patients with VHL Disease at the Clinical Centre to study how the molecular 9 landscape (Objective 1), the tumour microenvironment (TME) (Objective 2) and the metabolome 10 (Objective 3) promote or restrain cancer growth. 11 Methods: Subjects will be recruited to this prospective cohort study from the Urology Oncology 12 Branch at the National Cancer Institute. Growth kinetics of individual tumours will be tracked 13 radiologically. During procurement, tumours are identified and correlated with imaging. We will 14 perform multiparametric molecular profiling, integrating all datasets to achieve our study objectives. 15 Using next generation sequencing we will characterise the events that underlie malignant 16 transformation (Objective 1.1) and the molecular events associated with differential growth kinetics 17 (Objective 1.1). We will explore events associated with tumour fromation in extra-renal sites 18 (Objective 1.3) and how molecular/environmental variants influence variable phenotypic penetration 19 amongst VHL kindred (Objective 1.4). To assess the role of the TME, we will use genomic profiling to 20 assess the neoantigen landscape (Objective 2.1) and identify differential immune cell lineages using 21 RNA sequencing (Objective 2.2). We will validate these fidnings with multiplex immunohistochemistry 22 (IHC) approach. We will assess the perturbed metabolome utilising transcriptome profiling (Objective 23 3.1) and conduct a pilot study to assess genomic and transcriptomic changes with stable isotope- 24 resolved metabolic profiles obtained from VHL tumor tissue obtained intraoperatively. 25 Conclusion: This will be the most comprehensive molecular profiling of cancers arising in VHL 26 disease. It has the potential to address key questions regarding evolutionary cancer biology and to 27 identify the triggers for tumour growth and progression and hence predictive or prognostic biomarkers 28 which may have a wider relevance to cancer. It may inform novel therapeutic strategies for the 29 treatment and prevention of hereditary and sporadic ccRCC.