Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma

Abstract

Investigation of the genetic lesions underlying classical Hodgkin lymphoma (CHL) has been challenging due to the rarity of Hodgkin and Reed-Sternberg (HRS) cells, the pathognomonic neoplastic cells of CHL. In an effort to catalog more comprehensively recurrent copy number alterations occurring during oncogenesis, we investigated somatic alterations involved in CHL using whole-genome sequencing-mediated copy number analysis of purified HRS cells. We performed low-coverage sequencing of small numbers of intact HRS cells and paired non-neoplastic B lymphocytes isolated by flow cytometric cell sorting from 19 primary cases, as well as two commonly used HRS-derived cell lines (KM-H2 and L1236). We found that HRS cells contain strikingly fewer copy number abnormalities than CHL cell lines. A subset of cases displayed non-integral chromosomal copy number states, suggesting internal heterogeneity within the HRS cell population. Recurrent somatic copy number alterations involving known factors in CHL pathogenesis were identified (REL, the PD-1 pathway, and TNFAIP3). In eight cases (42%) we observed recurrent copy number loss of chr1:2,352,236-4,574,271, a region containing the candidate tumor suppressor TNFRSF14. Using flow cytometry, we demonstrated reduced TNFRSF14 expression in HRS cells from five of 22 additional cases (23%) and in two of three CHL cell lines. These studies suggest that TNFRSF14 dysregulation may contribute to the pathobiology of CHL in a subset of cases.

Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion

“…These data are of particular interest because we previously reported that HRS cell surface Figures 4A,D and 5). In addition to genetic alterations of MHC class I and class II antigen presentation pathway components, cHLs exhibited 1p36.32/TNFRSF14 copy loss as described 81 ( Figures 4A and 5). Of note, TNFRSF14 deficiency has been reported to disrupt B-and T-lymphocyte attenuator inhibitory T-cell signals and induce a tumor-supportive microenvironment in GC B-cell lymphomas ( Figure 5).…”

“…We identified 6 SCNAs (arm-level gain of 5p and 5q, focal loss of 1p36.32, 6p21.32, 6q23.3, and arm-level loss of 6q) that were recently described in DLBCL 26 as well as focal gain of 5p15.33 77,78 and focal loss of 6q12 79 that were reported in lung and prostate cancer, respectively. The focal region of 1p36.32 copy loss includes TNFRSF14 ( Figure 3A), 80,81 which is one of the most frequently mutated genes in GC-derived B-cell lymphomas. 26,82 Of interest, loss of TNFRSF14 and its encoded cell surface receptor HVEM leads to cell-autonomous B-cell activation and the development of GC B-cell lymphoma in vivo.…”

Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

“…Recently, recurrent losses of TNFRSF14 (herpesvirus entry mediator [HVEM]) have been described in cHL, 117 and previous studies in follicular lymphoma have provided evidence that loss of this receptor results not only in B-cell activation and proliferation but also in the induction of a tumor-supportive microenvironment. An elegant study conducted by Boice et al 118 showed that delivery of the HVEM ectodomain (soluble HVEM protein) by CD19 CAR T cells restored the tumor-suppressive effects of TNFRSF14 in a xenograft mouse model and that CAR T cells could be employed as "micropharmacies.…”

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

“…38 In this particular disease, highly sensitive techniques like dPCR and targeted NGS are essential to highlight low frequency mutations. High-throughput techniques such as low-coverage whole genome sequencing, 39 sequencing of circulating cfDNA 22 or targeted exome sequencing of isolated HRS cells 11 have recently helped to investigate genetic lesions underlying cHL, but sample sizes were very low. WES-based experiments of sorted Reed-Sternberg (RS) cells 11,40,41 recently identified new point mutations in cHL cases, including several mutations already reported in PMBL, such as CIITA, SOCS1, STAT6 and B2M mutations, as well as one case harboring the E571K XPO1 mutation, but this study was restricted to 10 cases, 11 with an insufficient median depth of sequencing (48X), which is potentially limiting for the discovery of genomic alterations.…”