828MO - Exonic mutation profile of primary gastrointestinal diffuse large B-cell lymphoma

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed.

Methods

We performed whole-exome sequencing of 53 matched tumor and normal samples from pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed.

Results

A total of 6848 protein-altering events were found in our pGI-DLBCL cohort, and among these identified recurrent genetic mutations, the five most frequent mutated genes were IGLL5 (47%), TP53 (42%), BTG2 (28%), IGHV2-70 (26%) and P2RY5 (26%). Through gene clustering analysis by DAVID algorithm, we found that the top 50 mutated genes of pGI-DLBCL were mostly enriched in pathways related to complement activation, immunoglobulin receptor binding and positive regulation of B-cell activation. Moreover, the nucleotide mutational signature analysis revealed that pGI-DLBCL mutation pattern was fitted with COSMIC signature 3, which had been implicated with the activation-induced cytidine deaminase during the pathogenesis of chronic lymphocytic leukemia. Compared with the nodal DLBCL, significantly less mutations were found within MYD88 (0%), EZH2 (0%) or BCL2 (2%) genes in pGI-DLBCL. In addition, when classified by the Han’s algorithm, patients of GCB type tended to have FAT4, GNAI2, TET2 and ID3 gene mutations. Notably, survival analysis result demonstrated that pGI-DLBCL patients with wild-type P2RY8 gene, an orphan Gα13-coupled receptor promoting the clustering of activated B cells, had a significantly longer overall survival time compared to those harboring its mutation after receiving tumor resection surgery plus Rituximab-based therapy.

Conclusions

Our study provides a comprehensive view of the exonic mutational landscape of pGI-DLBCL, within which a specific gene cluster was mutated relating to humoral immunity activation and P2RY8 mutation was associated with patient prognosis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Genetron Health, Inc., China.

Disclosure

All authors have declared no conflicts of interest.