Oncogenomic analysis of mycosis fungoides reveals major differences with Sézary syndrome. Homo sapiens

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is a malignancy of mature, skin-homing T cells. Sézary syndrome (Sz) is often considered to represent a leukemic phase of MF. In this study the pattern of numerical chromosomal alterations in MF tumor samples was defined using array-based CGH; simultaneously gene expression was analyzed using microarrays. Highly recurrent chromosomal alterations in MF include copy number gain of 7q36, 7q21-7q22 and loss of 5q13 and 9p21. This pattern characteristic of MF differs markedly from chromosomal alterations observed in Sz. Integration of data from array-based CGH and gene expression analysis yielded several candidate genes with potential relevance in the pathogenesis of MF. We confirmed that the FASTK and SKAP1 genes, residing in loci with recurrent gain, demonstrated increased expression. The RB1 and DLEU1 tumor suppressor genes showed diminished expression associated with loss. In addition, it was found that presence of chromosomal alterations on 9p21, 8q24 and 1q21-1q22 was associated with poor prognosis in patients with MF. This study provides novel insight into genetic alterations underlying MF. Furthermore, our analysis uncovered genomic differences between MF and Sz, which suggest that the molecular pathogenesis and therefore therapeutic requirements of these CTCLs may be distinct. To identify candidate oncogenes and tumor suppressor genes residing in chromosomal regions with recurrent copy number alteration in MF. To this end chromosomal alteration and gene expression patterns of 22 MF tumor samples were integrated to determine which genes located in minimal common regions (MCRs) with CNA demonstrated dysregulated expression associated with chromosomal alteration Keywords: aCGH and gene expression integration Overall design: 22 tumors for aCGH and gene expression

蕈样肉芽肿（Mycosis fungoides, MF）是最常见的皮肤T细胞淋巴瘤（cutaneous T-cell lymphoma, CTCL），为成熟皮肤归巢T细胞来源的恶性肿瘤。塞扎里综合征（Sézary syndrome, Sz）通常被视为MF的白血病阶段。本研究采用基于阵列的比较基因组杂交（array-based CGH）解析了MF肿瘤样本的染色体数目改变谱式，同时通过微阵列技术开展基因表达分析。MF中高频出现的染色体改变包括7q36、7q21-7q22的拷贝数增益，以及5q13和9p21的拷贝数缺失。该MF特征性染色体改变模式与塞扎里综合征中观察到的染色体改变存在显著差异。整合基于阵列的CGH与基因表达分析数据，筛选得到多个与MF发病机制潜在相关的候选基因。本研究验证了位于频发拷贝数增益区域内的FASTK和SKAP1基因存在表达上调现象；而RB1与DLEU1抑癌基因的表达下调则与其所在区域的染色体缺失相关。此外，本研究发现9p21、8q24及1q21-1q22区域的染色体改变与MF患者的不良预后显著相关。本研究为MF背后的遗传改变机制提供了全新视角。同时，本分析揭示了MF与塞扎里综合征之间的基因组差异，提示这两种皮肤T细胞淋巴瘤的分子发病机制乃至治疗需求可能存在显著区别。本研究旨在鉴定MF中存在频发拷贝数改变的染色体区域内的候选癌基因与抑癌基因。为此，我们整合了22例MF肿瘤样本的染色体改变与基因表达模式，以明确位于拷贝数改变（copy number alteration, CNA）最小共同区域（minimal common regions, MCRs）内的哪些基因呈现与染色体改变相关的表达失调。关键词：aCGH与基因表达整合 整体设计：22例肿瘤样本用于aCGH与基因表达分析。