CLINICOPATHOLOGICAL IMPLICATIONS OF RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA – A META-ANALYSIS: Abbreviated title: RHOA mutations in AITL

ABSTRACT Background: Studies have recently shown that RHOA mutations play a crucial role in angioimmunoblastic T-cell lymphoma (AITL) pathogenesis. We aimed to pool data from these studies to provide a comparison of clinicopathological features between the RHOA mutant and RHOA wild-type groups in the AITL population. Materials and Methods: We searched PubMed and Web of Science for the keywords "RHOA AND lymphoma" and selected only studies reporting the clinical significance of RHOA mutations in AITL. We calculated the odds ratios (OR) or the mean difference with 95% confidence intervals (CI), using a random-effect model. Results: Our pooled results showed a significant association between RHOA mutations and a T-follicular helper cell (TFH) phenotype, especially CD10 (OR=5.16; 95% CI: 2.32-11.46), IDH2 mutations (OR=10.70; 95% CI: 4.22 - 27.15), and TET2 mutations (OR=7.03; 95% CI: 2.14 - 23.12). Although DNMT3A together with TET2 and IDH2 mutations are epigenetic gene alterations, we found an insignificant association between RHOA and DNMT3A mutations (OR=1.72; 95% CI: 0.73 - 4.05). No significant associations of RHOA mutations with other clinicopathological features and overall survival were found. Conclusions: RHOA mutations are strongly correlated with a TFH phenotype and epigenetic mutations such as TET2 and IDH2. Further studies with large AITL samples should be conducted to validate the relationship of TET2, DNMT3A, and RHOA co-mutations.