Department of Dermatology, New York University School of Medicine, New York, New York, USA.
Cancer Res. 2011 Apr 1;71(7):2561-71. doi: 10.1158/0008-5472.CAN-10-2958. Epub 2011 Feb 22.
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM.
浅表扩散性黑色素瘤 (SSM) 和结节性黑色素瘤 (NM) 被认为代表了从放射状到垂直生长的线性进展的连续阶段。然而，有几条临床、病理和流行病学证据表明，SSM 和 NM 可能是肿瘤发展的独立途径的结果。我们利用一种综合基因组方法，将单核苷酸多态性阵列 (6.0; Affymetrix) 与基因表达阵列 (U133A 2.0; Affymetrix) 相结合，研究 SSM 和 NM 之间的分子差异。对 SSM 和 NM 之间表达差异最大的基因 (N = 114) 的通路分析显示，与代谢过程相关的显著差异。我们确定了 8 个基因 (DIS3、FGFR1OP、G3BP2、GALNT7、MTAP、SEC23IP、USO1 和 ZNF668)，其中 NM/SSM 特异性拷贝数改变与差异基因表达相关 (P < 0.05; Spearman 等级相关)。在两个外部数据集独立验证了 G3BP2、MTAP 和 SEC23IP 中 SSM 特异性基因组缺失。在 SSM 中过表达与代谢相关的基因 MTAP (甲基硫腺苷磷酸化酶) 可导致细胞生长减少。另一个与代谢相关的基因醛脱氢酶 7A1 (ALDH7A1) 的差异表达在使用人类黑色素瘤组织微阵列进行验证时在蛋白质水平上得到了验证。此外，我们表明 SSM 中 ALDH7A1 表达的降低可能是表观遗传修饰的结果。我们的数据揭示了 SSM 中存在而 NM 中不存在的反复发生的基因组缺失，这对黑色素瘤进展的线性模型提出了挑战。此外，我们的数据表明代谢相关基因调控的改变可能是 SSM 和 NM 不同临床行为的原因之一。
