Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations.

Abstract

Recent studies identified germline mutations in HAVCR2 (encoding TIM-3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2-wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 SPTCL patients diagnosed at eight Korean institutions was established. Whole-exome sequencing (WES) and RNA-seq were performed on eight patients in the discovery set. In the validation set, targeted gene sequencing (TGS) or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 24 (49.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (p = 0.001), development of hemophagocytic lymphohistiocytosis (HLH) or HLH-like systemic illness (p < 0.001), and short relapse-free survival (RFS) (p = 0.023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in TNF-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the mRNA and protein levels. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (p = 0.031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting SPTCL patients prognosis.