## 4 Discussion
were reported to promote cell growth or proliferation in different cancer types, suggesting that these lncRNAs may be involved at initial stages of tumorigenesis. However, many of these lncRNAs such as MAGII-IT1 may have roles during invasion and metastatic dissemination. The MCL International Prognostic Index (MIPI) is used for prognostication of MCL cases; however, the components of MIPI are not generally specific for cancer types. For example, high serum LDH levels may arise as a result of certain infections, anemia, or muscle trauma [92]. As older age is associated with poor survival of mantle cell lymphoma (Figure S3A), it was included as a component of the MIPI [10]. Interestingly, MIPI was not associated with MCL survival in our patient cohort, although older age was associated with inferior survival. This observation may be related to the lack of prognostic significance of other clinical variables that are components of MIPI, such as serum LDH levels (Figure S3D), in our MCL patients. RNA-Seq- or qRT-PCR-based quantification of prognocally significant transcripts (e.g., VWF or MRTG.153013.3) in MCL tumor tissues during routine clinical evaluations can potentially be used to improve prognostication of MCL cases during diagnosis. Consistent with the association of high VWF expression and shortened MCL survival, high expression of VWF may promote metastatic dissemination of the MCL tumor cells, as it was reported to promote metastasis in gastric adenocarcinoma [55] and breast cancer [93]. Many of the top overexpressed (e.g., FSTL1, TNS1, DDR2, or VWF) or underexpressed genes were suggested to promote invasion and/or metastasis in different cancer types. Genetic or epigenetic modulation of their expression may potentially prove effective against metastatic dissemination as long as these observations are reproduced in MCLs with in vitro or in vivo functional experiments. Alternatively, reconstitution of the expression of silenced tumor suppressor genes may inhibit cell proliferation and/or metastatic dissemination. Of note, preclinical studies showed that inhibition of VCAM1 may be an effective therapeutic option against pancreatic cancer [94]. Furthermore, inhibition of the PI3K pathway may be an effective strategy if the MCL cases with underexpression of PIK3 IP1 have constitutive activation of the PI3K signaling pathway. Importantly, there are clinical trials evaluating the efficacy of PI3K pathway inhibitors in MCL [91], and certain side-effects associated with PI3K pathway inhibitors may be reduced by selecting an appropriate subset of patients through the evaluation of PI3 KIP1 transcript expression in tumor samples of diagnostic MCL cases. Accumulating evidence suggests that tumor-infiltrating lymphocytes can be associated with clinical outcomes for patients of different cancer types including, but not limited to, cervical cancer [95], osteosarcoma [96], and breast cancer [97]. The observation that CD8+ T-cells were associated with poor overall survival of MCL patients is consistent with previous reports, indicating a poor prognostic role for these immunocytes [98; 99]. Given that MCL patients with abundant tumor-infiltrating CD8+ T-cells and low levels of FTX or PCA3 lncRNA can predict poorer overall survival (Figure 11), it may be possible to include WTS analysis during diagnosis to improve MCL prognostication. The observation that high CCND1 expression could identify a high-risk MCL group in the presence of infiltrating CD8+ T-cells (Figure S6) suggests that immunohistochemistry may potentially be applied for prognostication as long as these transcriptomic observations are reproduced at the protein level. Consistent with the reports on many other cancer types [100; 101], the abundance of eosinophils was associated with better overall survival for diagnostic MCL patients. Unlike CD8+ T-cells, tumor-infiltrating resting NK cells or eosinophils were not significantly associated with MCL survival when relapsed MM cases were included.