Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL

Abstract

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88 ^L265P , CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.

Figure 1

Copy number profile of TLBCL. Copy number profile (left panel) and copy number loss of heterozygosity (CN‐LOH) (right panel) of 43 TLBCL. On the y‐axis, the chromosomes are represented vertically from 1 to X (chromosome Y is excluded); on the x‐axis, the percentages of patients with CNA and CN‐LOH are shown with gains in blue, losses in red, and CN‐LOH in yellow. Regions with CNA and CN‐LOH frequency ≥10% and potential target genes are indicated.

Figure 2

Recurrent genomic alterations in TLBCL according to disease stage. The Oncoprint encompasses the 40 samples analyzed using next‐generation sequencing and copy number analysis. Each column represents one tumor sample, and each row represents one gene/region. Altered genes and genomic regions with a frequency ≥10% are ordered by decreasing frequency. From top to bottom: stage of the disease; COO by Hans’ algorithm and Lymph2Cx; MYC, BCL2, and BCL6 rearrangements; molecular subgroups according to LymphGen analysis; single nucleotide variants (SNVs), small insertions/deletions (indels), and copy number alterations (CNA). *Low coverage, higher probability of false positives.

Figure 3

Comparison of the copy number alterations (CNA) and mutation frequencies between testicular large B‐cell lymphoma (TLBCL), diffuse large B‐cell lymphoma (DLBCL), or primary large B‐cell lymphomas of the CNS (PCNSL). (A) Comparison of CNA between TLBCL cases and nodal DLBCL, highlighting biologically relevant regions with differential frequency (color denotes the enriched group). (B) A comparative plot of copy number alterations between TLBCL cases and PCNSL, highlighting the biologically relevant region with differential frequency. PCNSL CNA segments with lengths below 100 kbp were filtered out for this comparison. Frequent alterations in centromeric and telomeric regions and IG loci (IGK, IGH, and IGL) were displayed but not indicated as differentially altered regions since they were not filtered out in the PCNSL series. (C) Comparison of gene mutation frequencies between TLBCL, DLBCL, and PCNSL. Only genes mutated in more than 7.5% of the cases are shown. TLBCL mutations with VAF<10% were filtered out when comparing the TLBCL and PCNSL series, but not in the represented frequencies. *Denote several adjusted p‐value (Q‐value) thresholds when comparing the TLBCL series to the DLBCL or the PCNSL one.