Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma

Abstract

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 matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Results A total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were IGLL5 (47%), TP53 (42%), BTG2 (28%), P2RY8 (26%) and PCLO (23%). Compared to the common DLBCL, significantly less or absence of MYD88 (0%), EZH2 (0%), BCL2 (2%) or CD79B (8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the TP53 and LRP1B mutations, two established tumor suppressor genes in many human cancers. Moreover, IGLL5 and LRP1B mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL. Conclusions Our study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL.

Sequencing‐based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy

“…47 Recurrent alterations of LRP1B gene were also reported in different lymphoma subtypes, including diffuse large B-cell lymphoma (DLBCL), mucosa associated lymphoid tissue (MALT) lymphoma, transformation of follicular lymphoma to DLBCL, or primary central nervous system lymphomas (PCNSL). [48][49][50][51][52] Mutations of LRP1B correlated with a higher total mutational burden in patients with PCNSL, hepatocellular carcinoma, or melanoma. 51,53,54 In primary gastrointestinal DLBCL, mutations of LRP1B correlated with significantly worse OS.…”

“…Mutations of LRP1B correlated with a higher total mutational burden in patients with PCNSL, hepatocellular carcinoma, or melanoma 51,53,54 . In primary gastrointestinal DLBCL, mutations of LRP1B correlated with significantly worse OS 48 . Of note, LRP1B mutations correlated with favorable response to immune checkpoint inhibitors across diverse cancer types including DLBCL 55,56 .…”

“…51,53,54 In primary gastrointestinal DLBCL, mutations of LRP1B correlated with significantly worse OS. 48 Of note, LRP1B mutations correlated with favorable response to immune checkpoint inhibitors across diverse cancer types including DLBCL. 55,56 Despite that LRP1B belongs to established tumor suppressors, its precise role in the biology of MCL (and other lymphomas), and its potential application as a prognostic or predictive factor remain to be elucidated in larger patient cohorts and functional translational studies.…”

“…Inactivation of LRP1B by diverse genetic and epigenetic mechanisms belongs to the most frequent alternations in human cancer overall 47 . Recurrent alterations of LRP1B gene were also reported in different lymphoma subtypes, including diffuse large B‐cell lymphoma (DLBCL), mucosa associated lymphoid tissue (MALT) lymphoma, transformation of follicular lymphoma to DLBCL, or primary central nervous system lymphomas (PCNSL) 48–52 . Mutations of LRP1B correlated with a higher total mutational burden in patients with PCNSL, hepatocellular carcinoma, or melanoma 51,53,54 .…”

NTRK fusion protein expression is absent in a large cohort of diffuse large B-cell lymphoma

“…who performed a whole-exome sequencing of matched tumor tissues and blood samples from 53 patients with primary gastrointestinal diffuse large B-cell lymphoma. NTRK2 and NTRK3 were detectable in two and one sample, respectively ( 29 ). To detect NTRK fusions, several techniques are generally recommended by the ESMO Translational Research and Precision Medicine Working Group, including IHC, FISH, real-time polymerase-chain-reaction, and both RNA-based and DNA-based next-generation sequencing ( 13 ).…”