TERT epigenetic and genomic variants in stage II melanoma as biomarkers of outcome

项目摘要 与转移性黑色素瘤治疗的巨大进展相反，局部转移性黑色素瘤的治疗进展缓慢。 黑色素瘤没有进展超过肿瘤厚度和溃疡的组织形态学测量， 包括分级系统。这些指标对局部晚期、淋巴结阴性的 黑色素瘤（II期）通常较差。II期黑色素瘤的术后复发率在24%和25%之间。 从IIA期的46%降至IIC期的46%。与乳腺癌和结肠癌相反，分子病理学测试是 与常规组织病理学相比，常规用于提高疾病诊断的准确性， 有效的原发性黑色素瘤的分子检测，尽管商业实体声称相反。 最近，来自一项随机、安慰剂对照的pembrolizumab（一种抗PD-1药物）临床试验的数据显示， 免疫抑制剂，用于支持其作为手术切除的IIB期辅助治疗的批准 和IIC黑素瘤。尽管术后18个月随访的无复发生存率（RFS）显示， 与permbrolizumab相关的统计学显著获益，11例患者需要治疗以预防1例 复发这是因为安慰剂组的RFS相当高。考虑到 免疫疗法及其可变的疗效和高成本，我们需要更准确的工具来适当选择 患者进行治疗谁有肿瘤复发的可能性很高，和备用手术治愈的患者， 过度治疗的风险。这种方法的一个主要障碍是缺乏经过验证的生物标志物， 区分高风险和低风险患者。 一些出版物以及我们自己的初步数据支持上游调控区的改变 端粒酶逆转录酶基因（TERT）作为潜在的高价值预后生物标志物， 黑素瘤这些改变包括启动子区域中的热点突变（可能与启动子区域中的突变协同作用）。 遗传的种系变体）和/或上游调控区的甲基化。此外，大数据 已发表的研究表明，NRAS和可能的BRAF突变可能各自与降低的 II期黑色素瘤的存活率。在一些数据集中，如果突变与TERT同时发生，则效果更强 启动子突变目前的建议将测试的假设，增加分子测量的 TERT的上游调控区和NRAS或BRAF中的突变，单独或组合， 提高II期黑色素瘤复发预测模型的准确性。成功创建一个改进的 模型将引起外部团体的兴趣，以便在后续更大的多中心验证中进行合作， 临床效用研究，其中生物标志物最终可用于辅助治疗决策。

PROJECT SUMMARY In contrast to the dramatic progress in the treatment of metastatic melanoma, prognostication for localized melanoma has not advanced beyond the histomorphological measures of tumor thickness and ulceration that comprise the staging system. The prognostic accuracy of these measures for locally advanced, node-negative melanoma (Stage II) is generally poor. Post-surgical recurrence rates for stage II melanoma vary between 24% for stage IIA to 46% for stage IIC. In contrast to breast and colon cancers, where molecular pathology tests are routinely used to improve the accuracy of disease prognostication over routine histopathology, there are no validated molecular tests for primary melanoma, despite claims from commercial entities to the contrary. Recently, data from a randomized, placebo-controlled clinical trial of pembrolizumab, an anti-PD-1 immunotherapeutic agent, was used to support its approval as adjuvant therapy for surgically resected stage IIB and IIC melanoma. Although recurrence-free survival (RFS) at the 18-month post-surgical follow up showed a statistically significant benefit associated with permbrolizumab, 11 patients needed to be treated to prevent one recurrence. This is because the RFS in the placebo group is fairly high. Given the potential toxicity of immunotherapy, and its variable efficacy and high cost, we need more accurate tools to appropriately select patients for treatment who have a high probability of tumor recurrence, and spare surgically cured patients the risks of overtreatment. A major obstacle to this approach is the lack of validated biomarkers that accurately distinguish between high- and low-risk patients. Several publications as well as our own Preliminary Data support alterations of the upstream regulatory region of the telomerase reverse transcriptase gene (TERT) as potentially high-value prognostic biomarkers in melanoma. These alterations include hotspot mutations in the promoter region (possibly cooperating with an inherited germline variant), and/or methylation of an upstream regulatory region. In addition, data from large published studies suggest that NRAS, and possibly BRAF mutations may each be associated with decreased survival in stage II melanomas. In some datasets the effect is stronger if the mutations co-occur with TERT promoter mutations. The current proposal will test the hypothesis that adding molecular measurements of the upstream regulatory regions of TERT and mutations in NRAS or BRAF, either singly or in combination, will improve the accuracy of a recurrence prediction model for stage II melanoma. Successful creation of an improved model will generate interest from outside groups to collaborate on subsequent larger, multicenter validation and clinical utility studies where the biomarkers may eventually be used to assist in treatment decision-making.