Identification of Lethal Melanomas at the Time of Diagnosis

项目总结/摘要 黑色素瘤的发病率继续上升，而大多数其他癌症的发病率 拒绝了。进展为转移性黑色素瘤患者的新兴全身治疗 延长生存期，但可能有毒，成本高昂，疗效各异。有 努力将新药的使用扩展到疾病的早期阶段作为辅助治疗。更好 在诊断时预测致命的黑色素瘤对于确定那些 从辅助治疗中受益，相反，避免那些黑色素瘤 不太可能复发。我们的中心假设是，有可能确定 肿瘤样本中的遗传改变和免疫反应，这些改变和免疫反应决定了黑色素瘤可能是 如果不及早治疗最终会致命相反，我们假设有可能识别出 肿瘤的躯体轮廓表明复发和最终死亡的风险非常低， 患者，避免了对这些患者进行昂贵的毒性治疗的需要。我们还假设 宿主特征，包括多个基因的种系变异，将与 致命的黑素瘤在目标1中，我们将测试104个基因/基因中的常见体细胞突变是否 肿瘤中的区域与黑色素瘤的死亡有关。这些基因包括已知 致癌驱动因子（BRAF，NRAS和TERT）和肿瘤抑制因子（NF 1，CDKN 2A/CDKN 2B， PTEN和TP 53）。我们还将测试假设，测量免疫细胞环境将增加 信息的生存预测超出了传统的分级肿瘤浸润淋巴细胞。 然后，我们将探讨如何最好地结合联合收割机的遗传改变，免疫措施和2018年 美国癌症联合委员会（AJCC）的肿瘤分期，以确定这些黑色素瘤高度 最终可能致命在目标2中，我们将确定主机特性 生殖系变异，表型特征，阳光照射，年龄和性别之间存在差异， 黑色素瘤病例的特点是潜在的致命性与非致命性，导致确定 一个有致命性黑色素瘤高风险的人群亚群。这项研究将使用 这是一个独特的资源，适合于解决这些问题，国际，人口为基础的 基因、环境和黑色素瘤研究（GEM），收集了流行病学数据、病理学 和肿瘤切片的一个大队列的事件原发性皮肤黑色素瘤病例诊断 在2000年。我们有至少10年的生命状态和原因的随访 死亡的所有案件。创业板是一个理想的资源，因为后续期结束之前， 靶向和免疫治疗时代，使我们能够研究影响自然史的因素， 这种疾病绝大多数GEM病例（超过85%）表现为局部疾病， 我们预计，至少80%的死亡将发生在最初表现为局部或 区域性疾病。这些结果将增强我们在早期识别致命性黑色素瘤的能力。 阶段时，治疗可能更有效，相反，以确定黑色素瘤与一个非常 复发风险低，不必要的和潜在的毒性治疗可以确信 避免了

PROJECT SUMMARY/ABSTRACT Melanoma incidence rates continue to increase, whereas rates for most other cancers have declined. Emerging systemic therapies for patients who have progressed to metastatic melanoma are extending survival, but can be toxic, immensely costly and have variable efficacy. There are efforts to extend the use of new agents to earlier disease stages as adjuvant therapies. Better prediction of lethal melanoma at time of diagnosis is important to determine those who would benefit from adjuvant therapies and, conversely, avoid toxicity in those whose melanomas are unlikely to recur. Our central hypothesis is that it is possible to determine the combinations of genetic alterations and immune responses in tumor samples that define a melanoma likely to be ultimately lethal if not treated early. Conversely, we hypothesize that it will be possible to identify somatic profiles of the tumors that indicate a very low risk of recurrence and ultimate death of the patient, obviating the need for expensive, toxic treatments in such patients. We also hypothesize that host characteristics, including germline variants in multiple genes, will be associated with lethal melanoma. In Aim 1, we will test whether common somatic mutations in 104 genes/gene regions in tumors are associated with death from melanoma. These genes include known oncogenic drivers (BRAF, NRAS and TERT) and tumor suppressors (NF1, CDKN2A/CDKN2B, PTEN and TP53). We will also test the hypothesis that measuring the immune cell milieu will add information to survival prediction beyond conventional grading of tumor-infiltrating lymphocytes. We will then explore how best to combine the genetic alterations, immune measures and 2018 American Joint Committee on Cancer (AJCC) tumor stage to identify those melanomas highly likely to be ultimately lethal. In Aim 2, we will determine the extent to which the host characteristics of germline variants, phenotypic characteristics, sun exposure, age and gender differ among melanoma cases characterized as potentially lethal vs. nonlethal, leading to the identification of a subset of the population at high risk for lethal melanoma. This research will be undertaken using a resource that is uniquely suited to addressing these issues, the international, population-based Genes, Environment and Melanoma (GEM) Study, which collected epidemiologic data, pathology and tumor sections for a large cohort of incident primary cutaneous melanoma cases diagnosed in the year 2000. We have available a minimum of 10 years of follow-up of vital status and cause of death for all cases. GEM is an ideal resource because the end of the follow-up period precedes the targeted and immune therapy era, allowing us to study factors affecting the natural history of the disease. The vast majority of GEM cases (more than 85%) presented with local disease, and we project that at least 80% of the deaths will occur in cases initially presenting with local or regional disease. The results should enhance our ability to identify lethal melanomas at an early stage when treatments may be more effective and, conversely, to identify melanomas with a very low risk of recurrence for which unnecessary and potentially toxic treatments can be confidently avoided.