Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Abstract

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79–382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.

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

“…In accordance with the previous reports [ 17 ], our analysis of the pGI-DLBCL exome confirmed the high prevalence of mutations in the cell cycle and apoptosis regulatory pathway, with potential tumor driver mutations in TP53 (22/53), CCND3 (9/53) and MYC (8/53) in over 60% patients. TP53 mutations displayed a significantly increased frequency and MYD88 (0/53), NFKBIE (4/53) or CD79B (4/53) mutations were less or not found in our pGI-DLBCL cohort, suggesting that the pathogenesis of pGI-DLBCL were different from the nodal or other extranodal DLBCL, which relies on an activated NF-κB signaling pathway due to the common mutations in the above mentioned MYD88 , NFKBIE , or CD79B genes [ 26 ].…”

“…Recently, by analyzing a small group of patients using whole-exome sequencing (WES), a study by Li et al . has shed a light on the genetic mutations in pGI-DLBCL [ 17 ]. However, comprehensive research focusing on the mutational landscape of pGI-DLBCL, and the correlation between its genetic mutations and clinicopathological features are still rare.…”

A Novel Prognostic Model for Patients with Primary Gastric Diffuse Large B-Cell Lymphoma

“…As the data source, SEER, did not provide the IPI scores of the patients, we cannot compare this nomogram with the IPI scoring system. In addition, the results of this study ignored the genetic characteristics, which are now proved to be important in the diagnosis and prognosis of the disease [ 21 , 22 ]. Even so, our study remains an instructive and efficient model of PG-DLBCL prognosis.…”

Clinical and Molecular Characteristics of Rare Malignant Tumors of Colon and Rectum

“…Notably, the co-expression of the two gene products identifies an aggressive DLBCL subtype [ 6 ]. Other cytogenetic abnormalities involving also other histological forms (i.e., follicular type) are translocations of API2 (11q21), BCL2 (18q21), BCL6 (3q27), IGH (14q32), IGK (2p12), IGL (22q11), MYC (8q24), and MALT1 (18q21) [ 7 , 8 ]. The prognostic value of these genetic alterations in colorectal lymphomas is debated and under investigation.…”