Badal Brateil, Solovyov Alexander, Di Cecilia Serena, Chan Joseph Minhow, Chang Li-Wei, Iqbal Ramiz, Aydin Iraz T, Rajan Geena S, Chen Chen, Abbate Franco, Arora Kshitij S, Tanne Antoine, Gruber Stephen B, Johnson Timothy M, Fullen Douglas R, Raskin Leon, Phelps Robert, Bhardwaj Nina, Bernstein Emily, Ting David T, Brunner Georg, Schadt Eric E, Greenbaum Benjamin D, Celebi Julide Tok
Department of Pathology.
Department of Dermatology.
JCI Insight. 2017 May 4;2(9). doi: 10.1172/jci.insight.92102.
Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes.
We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions. We utilized a next-generation sequencing platform that enabled a comprehensive analysis of protein-coding and -noncoding RNA transcripts.
Gene expression changes unequivocally discriminated between benign and malignant states, and a dual epigenetic and immune signature emerged defining this transition. To our knowledge, we discovered previously unrecognized melanoma subtypes. A high-risk primary melanoma subset was distinguished by a 122-epigenetic gene signature ("epigenetic" cluster) and TP53 family gene deregulation (TP53, TP63, and TP73). This subtype associated with poor overall survival and showed enrichment of cell cycle genes. Noncoding repetitive element transcripts (LINEs, SINEs, and ERVs) that can result in immunostimulatory signals recapitulating a state of "viral mimicry" were significantly repressed. The high-risk subtype and its poor predictive characteristics were validated in several independent cohorts. Additionally, primary melanomas distinguished by specific immune signatures ("immune" clusters) were identified.
The TP53 family of genes and genes regulating the epigenetic machinery demonstrate strong prognostic and biological relevance during progression of early disease. Gene expression profiling of protein-coding and -noncoding RNA transcripts may be a better predictor for disease course in melanoma. This study outlines the transcriptional interplay of the cancer cell's epigenome with the immune milieu with potential for future therapeutic targeting.
National Institutes of Health (CA154683, CA158557, CA177940, CA087497-13), Tisch Cancer Institute, Melanoma Research Foundation, the Dow Family Charitable Foundation, and the Icahn School of Medicine at Mount Sinai.
黑色素瘤是一种异质性恶性肿瘤。我们旨在确定高危黑色素瘤的分子基础，即那些可能迅速进展、转移并导致不良预后的黑色素瘤。
我们使用一组78例未经治疗的黑素细胞肿瘤（包括皮肤原发性黑色素瘤和良性黑素细胞病变），研究了从良性状态到早期、中期和晚期肿瘤的转录组变化。我们利用了一个下一代测序平台，该平台能够对蛋白质编码和非编码RNA转录本进行全面分析。
基因表达变化明确区分了良性和恶性状态，并且出现了一种双重表观遗传和免疫特征来定义这种转变。据我们所知，我们发现了以前未被认识的黑色素瘤亚型。一个高危原发性黑色素瘤亚组的特征是有一个由122个表观遗传基因组成的特征（“表观遗传”簇）和TP53家族基因失调（TP53、TP63和TP73）。这种亚型与总体生存率低相关，并显示细胞周期基因富集。可导致免疫刺激信号并重现“病毒模拟”状态的非编码重复元件转录本（长散在核元件、短散在核元件和内源性逆转录病毒）被显著抑制。高危亚型及其不良预测特征在几个独立队列中得到了验证。此外，还鉴定了以特定免疫特征（“免疫”簇）为特征的原发性黑色素瘤。
TP53家族基因和调节表观遗传机制的基因在早期疾病进展过程中显示出很强的预后和生物学相关性。蛋白质编码和非编码RNA转录本的基因表达谱分析可能是黑色素瘤疾病进程的更好预测指标。本研究概述了癌细胞表观基因组与免疫环境之间的转录相互作用，具有未来治疗靶点的潜力。
美国国立卫生研究院（CA154683、CA158557、CA177940、CA087497 - 13）、 Tisch癌症研究所、黑色素瘤研究基金会、陶氏家族慈善基金会以及西奈山伊坎医学院。
