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

Esra Esmeray Sönmez; Tevfik Hatipoğlu; Deniz Kurşun; Xiaozhou Hu; Burcu Akman; Hongling Yuan; Ayça Erşen Danyeli; İnci Alacacıoğlu; Sermin Özkal; Aybüke Olgun; Taner Kemal Erdağ; Hua You; Can Küçük

doi:10.3390/cells11213394

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

Cells. 2022 Oct 27;11(21):3394. doi: 10.3390/cells11213394.

Authors

Esra Esmeray Sönmez^{1

2}, Tevfik Hatipoğlu^{1

2}, Deniz Kurşun^{1

2}, Xiaozhou Hu¹, Burcu Akman^{1

2}, Hongling Yuan^{1

3}, Ayça Erşen Danyeli^{4

5}, İnci Alacacıoğlu⁶, Sermin Özkal⁴, Aybüke Olgun^{6

7}, Taner Kemal Erdağ⁸, Hua You^{9

10}, Can Küçük^{1

2

11}

Affiliations

¹ İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir 35340, Türkiye.
² Basic and Translational Research Program, İzmir Biomedicine and Genome Center, İzmir 35340, Türkiye.
³ Department of Basic Oncology, Oncology Institute, Dokuz Eylül University, İzmir 35340, Türkiye.
⁴ Department of Pathology, Faculty of Medicine, Dokuz Eylül University, İzmir 35340, Türkiye.
⁵ Department of Pathology, Acıbadem University Altunizade Hospital, İstanbul 34662, Türkiye.
⁶ Department of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir 35340, Türkiye.
⁷ İzmir Tepecik Research and Training Hospital, Health Sciences University, İzmir 35020, Türkiye.
⁸ Department of Otorhinolaryngology, Faculty of Medicine, Dokuz Eylül University, İzmir 35340, Türkiye.
⁹ Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University, Chongqing 401122, China.
¹⁰ International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 401122, China.
¹¹ Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir 35340, Türkiye.

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 (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.

Keywords: WTS; alternative transcript; lncRNA; mRNA; mantle cell lymphoma; oncogene; prognosis; tumor microenvironment; tumor suppressor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Biomarkers, Tumor / genetics
CD8-Positive T-Lymphocytes / metabolism
Carcinogenesis
Exome Sequencing
Humans
Lymphocytes, Tumor-Infiltrating* / metabolism
Lymphoma, Mantle-Cell* / genetics
Prognosis
RNA, Long Noncoding* / genetics
RNA, Messenger / genetics
von Willebrand Factor

Substances

RNA, Long Noncoding
RNA, Messenger
von Willebrand Factor
Biomarkers, Tumor

Grants and funding

This research was funded by the Scientific and Technological Research Council of Turkey (TÜBİTAK) 3501 Career Development Program (CAREER), grant number 116S625 and the National Natural Science Foundation of China, grant number 81911530169.