Identification of Lethal Melanomas at the Time of Diagnosis

项目摘要/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 谢绝了。对进展为转移性黑色素瘤患者的新的系统治疗 可以延长存活期，但可能有毒，成本极高，疗效不一。确实有 努力将新药物的使用扩大到疾病的早期阶段，作为辅助治疗。更好 在诊断时对致命性黑色素瘤的预测对于确定哪些患者 从辅助治疗中受益，反之，避免那些黑色素瘤患者的毒性 不太可能复发。我们的中心假设是，有可能确定 肿瘤样本中定义黑色素瘤的基因改变和免疫反应可能是 如果不及早治疗，最终是致命的。相反，我们假设有可能发现 肿瘤的躯体特征表明肿瘤复发和最终死亡的风险非常低 患者，消除了对此类患者昂贵、有毒的治疗。我们还假设 宿主特征，包括多个基因中的生殖系变异，将与 致命的黑色素瘤。在目标1中，我们将测试104个基因/基因中常见的体细胞突变 肿瘤中的区域与黑色素瘤的死亡有关。这些基因包括已知的 致癌驱动因子(BRAF、NRAS和TERT)和肿瘤抑制因子(NF1、CDKN2A/CDKN2B、 PTEN和TP53)。我们还将测试这样一种假设，即测量免疫细胞环境将增加 肿瘤浸润性淋巴细胞常规分级以外的生存预测信息。 然后，我们将探索如何最好地将基因改变、免疫措施和2018年结合起来 美国癌症联合委员会(AJCC)肿瘤分期以高度识别这些黑色素瘤 很可能最终是致命的。在目标2中，我们将确定宿主特征在多大程度上 在生殖系变异中，表型特征、日照时间、年龄和性别在 黑色素瘤病例特征为潜在致命性与非致命性，导致确定 这是致命黑色素瘤高危人群的一部分。这项研究将使用以下方法进行 一个唯一适合解决这些问题的资源，即以人口为基础的国际 基因、环境和黑色素瘤(GEM)研究，收集流行病学数据、病理学 和肿瘤切片用于大量确诊的原发性皮肤黑色素瘤病例 在2000年。我们有至少10年的生命状况和病因随访 所有案件的死亡人数。创业板是一种理想的资源，因为跟踪期结束在此之前 靶向和免疫治疗时代，使我们能够研究影响人类自然病史的因素 这种疾病。绝大多数GEM病例(超过85%)以当地疾病为表现，以及 我们预计至少80%的死亡将发生在最初表现为当地或 区域性疾病。结果应该会增强我们在早期识别致命黑色素瘤的能力。 治疗可能更有效的阶段，相反，发现黑色素瘤时 复发风险低，不必要的和潜在的毒性治疗可以自信地进行 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.