The identification of genetic determinants of melanoma recurrence

 描述（由申请人提供）：与黑色素瘤相关的稳定高死亡率部分是由于预测黑色素瘤复发的局限性，特别是对于患有早期疾病的患者。虽然目前可用的临床病理学特征提供了一些信息，但其以更个性化的方式预测结果的能力有限。最近的研究提出了一些与黑色素瘤进展相关的分子预测因子，但这些预测因子过于笼统，无法满足个体患者的预后评估，仍需独立验证。我们研究的中心假设是，黑色素瘤复发是受调节的，但常见或罕见的生殖系遗传因素。我们推测，这些基因座将与临床上有利的黑色素瘤的早期复发风险相关，并且在表现为晚期至无复发的较不利的晚期阶段中可能具有保护作用。为了支持所提出的假设，我们已经产生了非常有希望的初步数据，证明生殖系遗传因素可能会影响黑色素瘤的临床结果。基于这些观察结果，我们提出了一个全面的遗传分析的生殖细胞和肿瘤标本的黑色素瘤患者在NYUMC确定，以确定新的生殖细胞遗传位点与黑色素瘤复发的风险。在具体目标1中，我们将对处于黑色素瘤复发极端的德系犹太人（AJ）早期黑色素瘤患者（I/II期）进行种系全基因组测序（WGS）和肿瘤全转录组测序（RNA-seq）：比较早期复发（n=100）与晚期或无复发（n=100）的患者。生殖细胞和肿瘤数据将整合到我们新开发的策略中，以确定与复发风险相关的生物学上最合理的候选人。AJ祖先的选择将通过减少遗传异质性和通过鉴定AJ患者中共有的与复发相关的创始者等位基因来增强分析能力来显著改善设计。在具体目标2中，我们将测试目标1中鉴定的遗传位点的关联性 在1,354例主要为非AJ欧洲血统的黑色素瘤患者队列中观察复发结局和其他临床指标。在特定目标3中，将在斑马鱼黑色素瘤模型中对与黑色素瘤复发相关的新型生殖系基因座进行功能测试，以鉴定在黑色素瘤进展和结局中具有生物学作用的靶向变体。将使用来自NYULMC亚组的1，268例黑素瘤患者的额外人群将新的种系变体/突变平行纳入预后黑素瘤模型中。本研究中产生的结果不仅将揭示具有更个性化临床潜力的黑色素瘤预后的新标志物，而且如所提出的，对其生物学作用的全面探索可能指向黑色素瘤进展中的新分子途径。因此，除了改善黑色素瘤早期患者的临床随访护理外，该研究的影响还在于发现了针对早期疾病但复发风险高的黑色素瘤患者定制的更个性化的辅助治疗的新靶点。

 DESCRIPTION (provided by applicant): The steadily high mortality associated with melanoma is in part due to the limitations of predicting the melanoma recurrence, especially for patients with early-stage disease. While currently available clinicopathological characteristics provide some information, their ability to predict outcome in a more personalized fashion is limited. Recent studies have proposed a number of molecular predictors in pathways related to melanoma progression, but these are too general to cater the prognostic assessment to individual patients and will still require independent validation. The central hypothesis of our study is that the melanoma recurrence is modulated but common or rare germline genetic factors. We postulate that such loci will be associated with the risk of early recurrence in clinically favorable melanomas, and potentially with protective effect in less favorable advanced stages manifesting with late to no relapse. In support of the proposed hypothesis we have generated highly promising preliminary data demonstrating that the germline genetic factors may impact melanoma clinical outcomes. Building on these observations we propose a comprehensive genetic profiling of germline and tumor specimens of melanoma patients ascertained at NYUMC to identify novel germline genetic loci associated with the risk of melanoma recurrence. In Specific Aim 1 we will perform germline whole-genome sequencing (WGS) and tumor whole-transcriptome sequencing (RNA-seq) on Ashkenazi Jewish (AJ) early stage melanoma patients (stage I/II) on extremes of melanoma recurrence: comparing patients with early recurrence (n=100) versus late or no recurrence (n=100). The germline and tumor data will be integrated in our newly developed strategy to identify biologically most plausible candidates associated with risk of recurrence. The selection of AJ ancestry will significantly improve the design by reducing the genetic heterogeneity and enhancing the analytical power by identification of founder alleles associated with recurrence, that are shared among AJ patients. In Specific Aim 2 we will test the identified genetic loci in Aim 1 for their association with recurrence outcomes and other clinical indicators in a melanoma cohort of 1,354 patients of predominantly non-AJ European ancestries. In Specific Aim 3, the novel germline loci associated with melanoma recurrence will be functionally tested in zebrafish melanoma model, identifying targetable variants with biological role in melanoma progression and outcome. The novel germline variants/mutations will be, in parallel, incorporated into prognostic melanoma model using an additional population of 1,268 melanoma patients from NYULMC subsets. The findings generated in this study will not only reveal novel markers of melanoma prognosis with more personalized clinical potential, but the comprehensive exploration of their biological role, as proposed, may point to novel molecular pathways in melanoma progression. Hence, besides improved clinical follow-up care of patients at early stage of melanoma, the study's impact is in the discovery of putatively novel targets of more personalized adjuvant therapies tailored for the melanoma patients with early disease but high risk of recurrence.