Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma

Abstract

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable–like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.

Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis

“…1 Recently, germline mutations causing loss of function of T-cell immunoglobulin mucin 3 (TIM-3) were identified in 60% to 85% of SPTCL patients. 6,7 In these patients, TIM-3 deficiency was shown to promote T-lymphocyte and -macrophage activation and the production of proinflammatory cytokines, challenging the malignant nature of skin T-lymphocyte infiltration. 6 Ruxolitinib is a selective JAK1/JAK2 inhibitor licensed for treatment of myelofibrosis and polycythemia vera in adults.…”

TIM3 comes of age as an inhibitory receptor

“…With regard to the debate whether TIM3 acts as an inhibitory or a stimulatory molecule, new evidence linking germline HAVCR2 mutations to human disease indicates that TIM3 acts as an inhibitory molecule [144][145][146] . It was shown that mutations in the TIM3 immunoglobulin V domain, c.245A>G (Tyr82Cys) and c.291A>G (Ile97Met), result in misfolding of TIM3 and loss of its expression on the cell surface of both T cells and myeloid cells.…”

“…Since the frequency of a homozygous Tyr82Cys mutation in the general population is estimated to be 1 in 35,000, this mutation likely confers high susceptibility to SPTCL 146 . Moreover, one patient with SPTCL carried a heterozygous Tyr82Cys mutation and an additional heterozygous mutation, Thr101Ile.…”

TIM‐3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis‐like T‐cell lymphoma and hemophagocytic lymphohistiocytosis

“…Sequencing of pre‐hematopoietic stem cell transplantation (pre‐HSCT) PBMC DNA retrospectively established the diagnosis of TIM‐3 deficiency caused by the compound heterozygous mutations p.Ile97Met and p.Thr101Ile in HAVCR2 (Figure S1A). While I97M has been described to abolish protein expression, 4 no expression or functional data have so far been published on the T101I mutation, which has been described in a single patient in association with the Y82C mutation 5 (Figure S1B). Flow cytometry revealed reduced TIM‐3 expression on activated T cells, illustrating that the T101I mutation also leads to reduced protein expression (Figure S1C).…”