Abstract
Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is typically an aggressive tumor in elderly patients. However, in a subset of young patients, EBV+ DLBCL follows a relatively indolent clinical course and exhibits a good response to chemotherapy. This lymphoma comprises polymorphous lymphoma and large cell lymphomas subtypes, with the latter subtype showing a significantly poorer prognosis. It is unknown whether the genetic background differs between age groups and histopathological subtypes. To investigate the genetic basis, heterogeneity, and recurrently mutated genes in EBV+ DLBCL, we performed whole-exome sequencing of DNA from 11 tissue samples of this lymphoma. Sequencing revealed that the most common substitution was the transition C>T/G>A. Genetic features—including the numbers of mutated genes in exonic region, single-nucleotide variants (SNV), and indels—did not significantly differ between age groups or histological subtypes. Matching with the COSMIC database revealed that the main mutational signature was signature 3, which is associated with failure of DNA double-strand break-repair by homologous recombination. Mutant-Allele Tumor Heterogeneity (MATH) scores showed that EBV+ DLBCL exhibited broad intratumor heterogeneity, and were positively correlated with Ann Arbor Stage and ≥2 extranodal lesion sites. We identified 57 selected recurrently mutated genes. The most commonly mutated five genes—LNP1 (11/11), PRSS3 (10/11), MUC3A (9/11), FADS6 (9/11), and TRAK1 (8/11)—were validated by Sanger sequencing. These mutated genes have not previously been identified. Overall, our present results demonstrate the tremendous genetic heterogeneity underlying EBV+ DLBCLs, and highlight the need for personalized therapeutic approaches to treating these patients.
Highlights
Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (EBV+ Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL), NOS) [1] constitutes 3–11% of all DLBCLs
We explored the mutational landscape of EBV+ DLBCL with the aim of identifying mutational signatures and tumor heterogeneity
Our main findings were the discoveries of four main signatures matched with the COSMIC database, and high intratumor heterogeneity as shown by Mutant-Allele Tumor Heterogeneity (MATH) scores that were significantly correlated with Ann Arbor stage and !2 extranodal lesion sites
Summary
Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (EBV+ DLBCL, NOS) [1] constitutes 3–11% of all DLBCLs. EBV+ DLBCL can occur in patients of any age, but elderly and young patients typically differ with regards to preferential lesion sites, morphological features, and prognosis. EBV+ DLBCL usually exhibits an aggressive clinical course with a median survival of 2 years or early relapse despite treatment with strong chemotherapy [2], while young patients typically present with nodal disease and better survival [3]. Hong et al [4] propose that EBV+ DLBCL in young patients might be a clinically distinct disease entity from EBV+ DLBCL of the elderly, likely involving mechanisms of lymphomagenesis other than immunosenescence. EBV+ DLBCL comprises polymorphous lymphoma (PL) and large cell lymphomas (LCL) subtypes, with a prominent inflammatory microenvironment and some degree of geographic necrosis. Compared to PL, the LCL subtype shows a significantly poorer prognosis [5]
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