Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL, and so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. To clarify the pathogenetic basis of pcALCL, we performed a high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g. ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first line skin-directed therapies or with extracutaneous disease.

中文翻译：

---

原发性皮肤间变性大细胞淋巴瘤的全基因组分析。

原发性皮肤间变性大细胞淋巴瘤 (pcALCL) 是一种由皮肤归巢 CD30+ 恶性 T 细胞引起的血液肿瘤，是原发性皮肤 CD30+ 淋巴组织增生性疾病谱系的一部分。迄今为止，仅在 pcALCL 中描述了少量的分子改变，并且到目前为止，还没有在患者中出现可以解释该疾病发病机制的明确统一主题。为了阐明 pcALCL 的发病机制，我们通过使用全基因组测序、全外显子组测序和 RNA 测序对该淋巴瘤（n = 12）进行了高分辨率遗传分析（基因组/转录组）。我们的研究揭示了这种恶性肿瘤背后的新基因组重排、拷贝数改变和小规模突变，揭示了细胞周期、T 细胞生理调节、通过 PI-3-K、MAPK 和 G 蛋白途径的转录和信号传导是 pcALCL 患者通常受分子改变影响的细胞过程。影响癌症相关基因的复发事件包括 PRDM1 和 TNFRSF14 的缺失、EZH2 和 TNFRSF8 的获得、LRP1B、PDPK1 和 PIK3R1 的小规模突变以及涉及 GPS2、LINC-PINT 和 TNK1 的重排。与基因组数据一致，转录组分析揭示了与 PI-3-K、MAPK 和 G 蛋白途径（例如 ERK、磷脂酶 C、AKT）相关的信号转导途径的上调。我们的分子研究结果表明，应探索抑制 pcALCL 中改变的增殖促进途径（特别是 PI-3-K/AKT 信号）作为这种淋巴瘤患者的潜在替代疗法，尤其是，