## 4 Discussion  
Mantle cell lymphoma is an aggressive but clinically heterogenous B-cell non-Hodgkin lymphoma, of which limited knowledge exists on the role of transcripts and tumor microenvironment in patient prognostication. The discovery of novel transcriptional or cellular prognostic biomarkers may potentially improve, and/or provide alternative methods for, the current clinical evaluations to achieve better patient management, including--but not limited to--stratifying patients for more effective therapeutic interventions. To identify prognostostally significant mRNAs, lncRNAs, and microenvironmental immunocytes, as well as to identify previously unknown MCL-associated genes in a comprehensive manner, we have applied WTS to a reasonably large cohort of mostly diagnostic MCL cases. Most previous studies focused on genomic alterations in MCL cases [18; 90]. Among a few reports on transcriptional alterations and pathogenesis of MCLs, certain cancer-related transcripts were identified. In a study involving a limited number of MCL cases, ROR1-AS1 was identified to be the most significantly overexpressed lncRNA compared to control samples. In vitro overexpression experiments revealed that ROR1-AS1 may promote cancerogenesis and decrease sensitivity to chemotherapy treatment [73]. Another study involving a few MCL cases, as well as MCL cell lines, reported lncRNAs associated with translation initiation complex by performing RNA immunoprecipitation (RIP)-seq [91]. Given the scarcity of transcriptomic studies focusing on the discovery of novel MCL-related genes,  
Figure 12: qRT-PCR cross-validates CCND1 and SNHG5 expression levels based on whole transcriptome sequencing. Box-and-whisker plots showing CCND1 mRNA WTS (**A**) and qRT-PCR (**B**) expression levels in MCL cases and control B-cell subsets. Box-and-whisker plots representing SNHG5 lncRNA WTS (**C**) and qRT-PCR (**D**). Linear correlation graphics comparing relative expression levels based on whole transcriptome sequencing and qRT-PCR for CCND1 mRNA (**E**) or SNHG5 lncRNA (**F**). CCND1 linear correlation graphic involves one value for each of NBC, MBC, and CC B-cell subsets as well as values for 24 MCL tumor tissue samples. SNHG5 linear correlation graphic involves the same set of control sample values in addition to 22 MCL tumor tissue samples. WTS: whole transcriptome sequencing; R: Pearson product-moment correlation. we hypothesized that upregulated or downregulated protein-coding transcripts and lncRNAs can act as oncogenes or tumor suppressor genes in MCL if they are also implicated in other cancer types. As expected, CCND1 was one of the top oncogene candidates identified in MCL tumors confirming previous studies for constitutive overexpression of CCND1 as an initial cancer-associated alteration that promotes uncontrolled proliferation [8]. Top underexpressed tumor suppressor candidates such as UBXN1, HNRNPA1, PPP1R15A, and LAPTM5 may also be contributing to tumor tissue formation through inhibition of apoptosis at initial stages of cancerogenesis (Table 2). Top differentially expressed alternative transcripts may be involved in evasion of tumor cells from CD8+T-cell attack through deregulation of antigen loading and presentation [9]. Interestingly, 7 of the top 10 oncogene candidate protein-coding genes identified (e.g., FSTL1, VCAM1, VWF) were shown in other cancer types to promote cell migration, invasion, or metastasis. Consistent with this finding, the top differentially expressed protein-coding genes enriched in MCL tumors were related either to the interaction of tumor cells with the extracellular matrix or promotion of invasion and metastasis, mainly through constitutive activation of MET signaling (Figure 4A). Transcriptional dysregulation of several metastasis-associated genes seems to play a critical role in dissemination of MCL tumor cells to distant sites such as bone marrow, liver, and spleen. Many of the top oncogene candidate lncRNAs (MIR100 HG, LINC01268, FTX, etc.)