肿瘤细胞治疗研究
英文原题：Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma.
MCL肿瘤中致癌相关转录物的表达水平和/或微环境免疫细胞的比例可用于改善预后判断，从而实现更好的患者管理和治疗结果。
套细胞淋巴瘤（MCL）是一种侵袭性B细胞非霍奇金淋巴瘤（NHL）亚型，以CCND1和SOX11基因过表达为特征。尽管近年来治疗方法有所改善，但该病通常与临床不良预后相关。与MCL发生和预后相关的基因在很大程度上仍不清楚。通过全转录组测序（WTS），我们鉴定了MCL病例与反应性扁桃体B细胞亚群相比差异表达的mRNA、lncRNA和可变转录本。CCND1、VCAM1和VWF mRNA，以及MIR100HG和ROR1-AS1 lncRNA，位列前10位最显著过表达且与肿瘤发生相关的转录本之中。对每个前位上调和转录本进行的生存分析显示，VWF mRNA高表达和FTX lncRNA低表达的MCL病例与较差的总生存期相关。同样，过表达的可变转录本MSTRG.153013.3高表达与MCL生存期缩短相关。已知的候选肿瘤抑制因子（如PI3KIP1、UBXN）在MCL病例中显著下调。前位差异表达的蛋白编码基因富集于与侵袭和转移相关的信号通路。基于CIBERSORTx估计的肿瘤浸润免疫细胞丰度进行的生存分析显示，CD8+ T细胞或静息NK细胞比例高以及嗜酸性粒细胞比例低与诊断时MCL病例较差的总生存期相关。对肿瘤浸润CD8+ T细胞丰度与过表达候选癌基因的整合分析显示，CD8+ T细胞比例高且FTX或PCA3低表达的MCL病例可能有助于预测高危MCL患者。WTS结果通过选定转录本的qRT-PCR以及线性相关分析进行了交叉验证。总之，MCL肿瘤中致癌相关转录本的表达水平和/或微环境免疫细胞的比例可用于改善预后判断，从而实现更好的患者管理和结局。
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8 + T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8 + T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8 + T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.
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