Objective
Recent work in our lab revealed the epigenetic repression of the tumor suppressor RASSF4 in the incurable plasma cell malignancy multiple myeloma (MM). This correlated with disease progression and poor overall survival. RASSF4 overexpression in MM cells sensitized them to bortezomib and trametinib, proteasome and MEK1/2 inhibitors, respectively. In the current study, we will investigate the prognostic value of RASSF4 expression on overall survival in the B cell malignancies diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
Methods
Publicly available gene expression profiling data of two independent cohorts of DLBCL patients and one cohort of MCL patients was used, as well as expression data of cell lines. Significance in difference of overall survival was determined with Mantel-Cox analysis. Cox analysis allowed us to assess the value of RASSF4 expression as an independent prognostic factor for overall survival in R-CHOP treated DLBCL patients. 

Results
It became apparent that high RASSF4 expressors benefit from significantly higher overall survival in DLBCL (p = 0,007), especially in R-CHOP treated patients. In contrast, no improvement in clinical outcome was observed in MCL. In the multivariate analysis RASSF4 surfaced as an independent prognostic factor (p = 0,047) in R-CHOP treated DLBCL patients. In addition, we found that in these patients 88% of low RASSF4 expressors show a complex karyotype, compared to 57% of high RASSF4 expressors (p = 0,019). 

Conclusion
Together, our data suggest that RASSF4 is also a tumor suppressor in DLBCL and loss of RASSF4 favors disease progression. Moreover, our data suggest that RASSF4 is a new predictive marker for response to R-CHOP treatment. These findings thus provide the rationale for future preclinical studies studying the epigenetic regulation of RASSF4 and its role in DLBCL pathogenesis.

Loss of the tumor suppressor RASSF4 is associated with aggressive disease and poor outcome in Diffuse Large B Cell Lymphoma