Mantle cell lymphoma (MCL) is a rare, aggressive and incurable type of cancer with a high incidence of systemic dissemination and a median survival time of 3-4 years. Understanding the genetics and biology of MCL are necessary for the development of better biomarkers and novel targets of therapies. A limited number of sequencing studies were performed on MCL recently, which improved the knowledge on causal mutations and molecular mechanisms of MCL. However, the small cohort sizes of these studies and use of outdated computational tools and databases limited the findings of these studies. The objective of our study was to identify the genetic alterations and molecular pathways that are associated with the development, progression, and dissemination of MCL by using leading-edge bioinformatics tools, up-to-date molecular biology databases, and a large sample size. Presented here is a meta-analysis of whole exome sequencing data from tumor biopsies of 67 MCL patients, which resulted in the identification of several novel gene targets of recurrent mutations in MCL such as SP140, S1PR1, PTPRD, HNRNPH1, LRP1B, FAT1, MAP3K14, and DST. Our analysis revealed four mutation hotspots in the first exons of MAP3K14 with predicted activating impact on the protein in MCL, and five other types of B-cell lymphoma and leukemia. We further proposed that the recurrent mutations of MAP3K14 are potentially associated with a higher likelihood of relapse, because of their emergence in relapse biopsies of four patients. This finding suggests that the recurrent mutations of MAP3K14 may have application for prediction of disease outcome, response to therapy, and transformation of the indolent variant of MCL to the more aggressive subtype.Finally, we detected a significant accumulation of mutations in signaling pathways with roles in mechanisms of tumor metastasis, such as Rho GTPase mediated signaling, focal adhesion, G-protein coupled receptor signaling, cAMP-PKA signaling, ERK-MAPK signaling, ROBO-Slit signaling, and JAK-STAT signaling. These findings offer new insights into the understanding of driver mutations and molecular mechanisms underlying the aggressive clinical course of MCL and may have implications for the development of therapies.
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Thesis advisor: Paetzel, Mark
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