Targeted sequencing of 76 uniformely treated primary DLBCL samples

Background/Purpose: Recently, the mutational background of diffuse-large B-cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g. IPI) are insufficient, particularly in identifying patients with poor prognosis who would benefit from alternative treatments.Methods: We investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival at 2 years (EFS). Secondary endpoints included progression-free (PFS) and overall survival (OS). Targeted high throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B-cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations.Results: Targeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13 and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS, while SOCS1 mutations were associated with better PFS. In multivariable analysis, CREBBP and EP300 mutations remained significant for predicting worse OS when IPI and failure to achieve complete remission were taken into account.Conclusion: Targeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identified tumor-based genetic prognostic markers that could be useful in clinical management of such patients.