Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns

Abstract

Follicular lymphoma (FL) accounts for approximately 20% of all new lymphoma cases. Increases in cytological grade are a feature of the clinical progression of this malignancy, and eventual histologic transformation (HT) to the aggressive diffuse large B-cell lymphoma (DLBCL) occurs in up to 15% of patients. Clinical or genetic features to predict the risk and timing of HT have not been comprehensively described. In this study, we analyzed whole genome sequencing data from 423 patients to compare the protein coding and non-coding mutation landscapes of untransformed FL, transformed FL and de novo DLBCL. This revealed two genetically distinct subgroups of FL which we have named DLBCL-like (dFL) and constrained FL (cFL). Each subgroup has distinguishing mutational patterns, aberrant somatic hypermutation rates, biological, and clinical characteristics. We implemented a machine-learning-derived classification approach to stratify FL patients into cFL and dFL subgroups based on their genomic features. Using separate validation cohorts, we demonstrate that cFL status, whether assigned with this full classifier or a single-gene approximation, is associated with a reduced rate of HT. This implies distinct biological features of cFL that constrain its evolution and we highlight the potential for this classification to predict HT from genetic features present at diagnosis.

Unexpected MYC::DMD translocation after transformation of follicular lymphoma with IGH::BCL2 and IGH::MYC

“…4 The other is a case included in a recently published large series in which a FL had a MYC::DMD translocation but the paired histologically transformed lymphoma had a discordant IGH::MYC. 5 This sequence of events is opposite to what is reported in this case, but together these cases highlight that detection of a MYC rearrangement in synchronous or metachronous lymphomas using break apart FISH probes cannot be assumed to represent the same translocation or be used as evidence of direct clonal relatedness. In fact, the discordant MYC rearrangements in the FL and HGBCL portions of these lymphomas provide strong evidence of branched molecular/cytogenetic evolution, a feature that is well documented in FL transformation.…”

“…Immunoglobulin light chain stains showed kappa restriction with increased cytoplasmic reactivity (Figure 1H-I). Classical cytogenetic analysis revealed the following karyotype: 47-52,XY,+del(X) (p22.1p22.3),add(3)(q27),+5,+7,+8,+10,der(11)t(2;11) (p13;q25),+12, t(14;18)(q32;q21),+21[cp6]/46,XY [5]. Trisomy 8 was identified, but abnormalities specifically involving 8q24 were not.…”

Revisiting Reddy: A DLBCL Do-over

“…Specifically, the comparison cohort in Tumor exomes were analyzed for somatic mutations using a combination of four modern variant callers, an approach that we have previously shown to perform favorably on data from formalin-fixed paraffin embedded (FFPE) tissue. 20,21 The variants reported by Reddy were converted from the wide tabular format into a long MAF-like tabular format for subsequent analyses. The read support for each variant was added using a custom Python script that relies on pysam (https://github.com/LCR-BCCRC/lcr-scripts/tree/master/augment_ssm/1.0).…”