Identification of Somatic Mutations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type by Massive Parallel Sequencing

Abstract

To determine whether the mutational profile of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is unique by comparison with other diffuse large B-cell lymphoma subtypes, we analyzed a total cohort of 20 PCLBCL-LT patients by using next-generation sequencing with a lymphoma panel designed for diffuse large B-cell lymphoma. We also analyzed 12 pairs of tumor and control DNA samples by whole-exome sequencing, which led us to perform resequencing of three selected genes not included in the lymphoma panel: TBL1XR1, KLHL6, and IKZF3. Our study clearly identifies an original mutational landscape of PCLBCL-LT with a very restricted set of highly recurrent mutations (>40%) involving MYD88 (p.L265P variant), PIM1, and CD79B. Other genes involved in B-cell signaling, NF-κB activation, or DNA modeling were found altered, notably TBL1XR1 (33%), MYC (26%) CREBBP (26%), and IRF4 (21%) or HIST1H1E (41%). MYD88 variant was associated with copy number variations or copy neutral loss of heterozygosity in 60% of patients. The most frequent genetic losses involved CDKN2A/2B, TNFAIP3/A20, PRDM1, TCF3, and CIITA. Together, these results show that PCLBCL-LT exhibits a unique mutational landscape, combining highly recurrent hotspot mutations in genes involved in NF-kB and B-cell signaling pathways, which provides a rationale for using selective inhibitors of the B-cell receptor.

Cutaneous B‐cell lymphomas: 2019 update on diagnosis, risk stratification, and management

“…Most cases are MUM‐1/IRF‐4 and bcl‐6 positive, CD10 negative, and have a gene expression profile resembling activated B cells . Perhaps not surprisingly, the genetic landscape observed in PCDLBCL, LT is similar to that observed in activated B‐cell‐type diffuse large B‐cell lymphoma (ABC‐DLBCL), with NF‐κB‐activating mutations being observed in CD79B, CARD11, and MYD88 . Of these, somatic MYD88 L265P mutations appear most common with a prevalence rate of ≈75% .…”

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma

“…In contrast, a SOCS1 mutation was detected in the tumor of subcutaneous tissue in TP44 (). SOCS1 mutations are known to be more prevalent in primary cutaneous diffuse large B‐cell lymphoma, leg type compared to DLBCL NOS . Therefore, somatic mutations in these genes may bias the location of tumors.…”

“…SOCS1 mutations are known to be more prevalent in primary cutaneous diffuse large B-cell lymphoma, leg type compared to DLBCL NOS. 18 Therefore, somatic mutations in these genes may bias the location of tumors. These results suggest that the paired tumors originate from divergent evolution of CPC through accumulation of distinct mutations.…”

“…Recent studies have proposed that primary and relapsed tumors in several hematological cancers may arise from CPC. 6,7,[18][19][20] Previously, it was reported that the dominant clones were identical in paired tumors of primary and relapsed MCL and FL according to the VDJ coding joints, suggesting that CPC may arise after F I G U R E 6 Stages of divergence from common precursor cells to tumors. Black arrows indicate the clonal pathway between samples.…”

Rituximab, lenalidomide and pembrolizumab in refractory primary cutaneous diffuse large B‐cell lymphoma, leg type

“…Fluorescence in situ hybridisation analysis was positive for MYC gene locus rearrangement (Schrader et al , ; Zhou et al , ) and revealed clonal copy number gains of MYC and BCL2 . Monoclonal rearrangement of immunoglobulin heavy ( IGH ) chain was found and mutational analysis revealed a KRAS point mutation p.A146V, but MYD88 was not mutated (Mareschal et al , ). Whole‐body positron emission tomography/computed tomography excluded any lymph node or visceral involvement.…”