Study

Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T-cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Study ID Alternative Stable ID Type
EGAS00001002765 Other

Study Description

Sub-cutaneous panniculitis-like T-cell lymphomas (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation which adversely impacts survival1,2. T-cell-immunoglobulin mucin-3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants in highly conserved residues of TIM-3, c.245A>G(p.Y82C) and c.291A>G(p.I97M), each with specific geographic distribution. Y82C-TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while I97M-TIM-3 occurs in Caucasians. Both variants induce protein misfolding and abrogate TIM-3’s plasma-membrane expression leading to persistent immune activation, increased production of inflammatory cytokines, including TNF-α and IL-1β, promoting HLH and SPTCL. Our findings highlight HLH/SPTCL as a new genetic entity and showcase TIM-3 mutations as the first causative genetic defect in SPTCL. While TIM-3-mutant HLH/SPTCL ... (Show More)

Study Datasets 1 dataset.

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Dataset ID Description Technology Samples
EGAD00001004310
Whole exome sequencing data of 17 SPTCL cases, including 7 matched-normal samples.
Illumina HiSeq 2500,Illumina HiSeq 4000 24

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