Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma

Abstract

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B , GNA13 and POU2AF1 , which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo- diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2 , DTX1 , UBE2A and HIST1H1E . The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.

Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma

“…The study population (PdH cohort) consisted of 84 DLBCL patients, diagnosed in Spanish medical institutions between 2002 and 2016. Five of the patients (PDLB63-PDLB67) had a diagnosis of DLBCL after a histological transformation of follicular lymphoma without treatment prior to transformation 33 . Formalin-fixed, paraffin-embedded tissue (FFPET) sections from diagnostic biopsies were collected.…”

“…Two SureSelect target enrichment custom panels were designed using the SureDesign (Agilent Technologies, Santa Clara, CA, USA) web-based tool (earray.chem.agilent.com/suredesign/). The genes included are involved in lymphomagenesis-relevant pathways and were selected based on previous studies 17 , 18 , 34 – 37 and our earlier findings 33 . The designs covered the coding exons of the selected genes.…”

Precision medicine for human cancers with Notch signaling dysregulation (Review)

“…Notch signaling molecules are frequently altered in T-ALL (80%) (53) and microsatellite-instable (MSI) or dNA polymerase-ε catalytic subunit A (POLE)-mutant subtypes of gastric and esophageal cancer (79%), colorectal cancer (70%) and uterine corpus endometrial cancer (64%) (54). Notch signaling is activated owing to gain-of-function (GoF) NOTCH alterations in T-ALL (55)(56)(57), chronic lymphocytic leukemia (58,59), diffuse large B cell lymphoma (60,61), mantle cell lymphoma (62), breast cancer (63)(64)(65) and non-small-cell lung cancer (NScLc) (66) as well as loss-of-function (LoF) FBXW7 mutations in MSI or POLE-mutant cancers and hematological malignancies (53,54) (Fig. 2).…”

“…In HNScc, tumor-suppressive Notch signaling is inactivated owing to LoF NOTCH1 mutations, but oncogenic Notch signaling is activated by JAG1, JAG2 or NOTCH3 upregulation (69,89). Tumor-suppressive Notch signaling is advantageous for maintaining a non-cancerous esophagus in middle-aged or elderly individuals (71), whereas oncogenic Notch signaling promotes the later stages of T-cell leukemogenesis (57) and B-cell lymphomagenesis (61). Because Notch signals intrinsically exert both oncogenic and tumor-suppressive effects ( Fig.…”

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

“…However, the proliferative capacity of FL cells increases gradually with the FL grade. FL progression requires the supporting infrastructure of the follicular TME to maintain survival, a requirement that gets progressively lost in the process of transformation to aggressive DLBCL ( 248 , 249 ). Follicular dendritic cells (FDCs) are one branch of this supporting infrastructure.…”