Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma

Abstract

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, 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.

Long non‐coding RNA as a novel biomarker and therapeutic target in aggressive B‐cell non‐Hodgkin lymphoma: A systematic review

“…Among the top 20 dysregulated lncRNAs, low expression of FTX was associated with poor OS. Based on this study lncRNAs play a role in MCL pathogenesis mostly via epidermal growth factor (EGF) receptor, Wnt and mammalian target of rapamycin (mTOR) signalling pathways 58 . Among lncRNAs with a diagnostic value, lncRNAs GATA6‐AS 59 and MORT 61 were downregulated, and lncRNAs MANCR 64 and LINK‐A 65 were upregulated.…”

“…Eight studies assessed the role of lncRNAs in patients with MCL 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 (Table 4 ). A WTS study demonstrated that 1067 lncRNAs were upregulated and 989 lncRNAs were downregulated in patients with MCL.…”

“…Based on this study lncRNAs play a role in MCL pathogenesis mostly via epidermal growth factor (EGF) receptor, Wnt and mammalian target of rapamycin (mTOR) signalling pathways. 58 Among lncRNAs with a diagnostic value, lncRNAs GATA6‐AS 59 and MORT 61 were downregulated, and lncRNAs MANCR 64 and LINK‐A 65 were upregulated. These lncRNAs play their role in MCL pathogenesis by regulating survivin expression (LINK‐A), glucose uptake (GATA6‐AS), miRNA‐16 expression (MORT), inducing cell proliferation (MANCR, LINK‐A) and inhibiting apoptosis (LINK‐A).…”

“…Based on this study lncRNAs play a role in MCL pathogenesis mostly via epidermal growth factor (EGF) receptor, Wnt and mammalian target of rapamycin (mTOR) signalling pathways. 58 Among lncRNAs with a diagnostic value, lncR-NAs GATA6-AS 59 and MORT 61 were downregulated, and lncRNAs MANCR 64 and LINK-A 65 1.496, 95% CI [1.119-1.831]) was associated with poor OS (Table 3).…”