The identification of genetic determinants of melanoma recurrence

 描述(申请人提供)：与黑色素瘤相关的高死亡率在一定程度上是由于预测黑色素瘤复发的局限性，特别是对于早期疾病的患者。虽然目前可用的临床病理特征提供了一些信息，但它们以更个性化的方式预测结果的能力是有限的。最近的研究已经提出了一些与黑色素瘤进展相关的分子预测因子，但这些太笼统，不能满足单个患者的预后评估，仍需要独立验证。我们研究的中心假设是黑色素瘤的复发是调节的，但常见或罕见的生殖系遗传因素。我们推测，在临床有利的黑色素瘤中，这种基因座与早期复发的风险有关，而在较不利的晚期表现为晚期或无复发时，这种基因座可能与保护性作用有关。为了支持提出的假设，我们产生了非常有希望的初步数据，证明生殖系遗传因素可能影响黑色素瘤的临床结果。在这些观察的基础上，我们建议对在NYUMC确定的黑色素瘤患者的种系和肿瘤标本进行全面的遗传图谱分析，以确定与黑色素瘤复发风险相关的新的种系遗传位点。在具体目标1中，我们将对德系犹太人(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)，比较黑色素瘤复发的极端情况：早期复发患者(n=100)与晚期或无复发患者(n=100)。生殖系和肿瘤数据将被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可信的候选对象。AJ血统的选择将显著改善设计，减少遗传异质性，并通过识别与复发相关的创始人等位基因来增强分析能力，这些等位基因在AJ患者中共享。在特定的目标2中，我们将测试目标1中已识别的遗传基因座的关联性 在以非AJ欧洲血统为主的1,354名黑色素瘤患者的队列中，复发结果和其他临床指标。在具体目标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的生殖系基因座进行功能测试，以确定在黑色素瘤进展和结果中具有生物学作用的靶向变异。新的生殖系变异/突变将被并入到预后黑色素瘤模型中，使用来自NYULMC亚群的额外1,268名黑色素瘤患者。这项研究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记物，而且如所建议的那样，对其生物学作用的全面探索可能指向黑色素瘤进展的新的分子途径。因此，除了改善对黑色素瘤早期患者的临床随访护理外，这项研究的影响还在于发现了为具有早期疾病但复发风险高的黑色素瘤患者量身定做的更个性化辅助治疗的假定新靶点。

 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.