Molecular Profiling Reveals Low- and High-Grade Forms of Primary Melanoma
Molecular Profiling Reveals Low- and High-Grade Forms of Primary Melanoma
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DOI：
10.1158/1078-0432.ccr-12-0343
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发表时间：
2012-08-01
影响因子：
11.5
通讯作者：
Jonsson, Goran
中科院分区：
文献类型：
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作者：
Harbst, Katja;Staaf, Johan;Jonsson, Goran
目的：对于原发性黑色素瘤，肿瘤厚度、有丝分裂率和溃疡形成是其诊断的基础。然而，黑色素瘤侵袭性的分子暴露严重缺失。我们最近在转移性黑色素瘤中发现了一种四级结构，它可以预测结果并为生物学提供信息。这提出了一种可能性，即即使在黑色素瘤的早期阶段也存在分子结构，并且分子决定因素可能是组织表型和最终患者outcome.Experimental设计的基础：我们对223例存档的原发性黑色素瘤进行了RNA表达、238处病变的致癌突变、组织形态计量学和生存数据的水平整合分析。我们以前描述的四类结构，阐明了在转移性病变是明显的表达空间内的原发性黑色素瘤。因为这些亚类汇聚成两个更大的预后和表型组，我们使用转移性病变来开发能够区分疾病的“高”和“低”等级形式的基于二进制亚型的签名。随后将两级签名应用于原发性黑色素瘤。与低级别肿瘤相比，高级别原发性黑色素瘤与肿瘤厚度、有丝分裂率、溃疡形成（均P < 0.01）、无复发生存率（HR = 4.94; 95%CI，2.84-8.59）和总生存率（HR 3.66; 95%CI，2.40-5.58）显著相关。高级别黑色素瘤表现出增殖和BRCA 1/DNA损伤信号基因水平升高，而低级别病变则具有较高的免疫基因表达。重要的是，在两个外部的基因表达datasets.Conclusions的分子级签名进行了验证：我们提供的证据黑色素瘤内的分子组织，这是保存在所有阶段的疾病。临床癌症研究; 18（15）; 4026-36。（C）2012年AACR。
Purpose: For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.Experimental Design: We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Results: Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.Conclusions: We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease. Clin Cancer Res; 18(15); 4026-36. (C)2012 AACR.