The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome

Abstract

Sézary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4 positive T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 Sézary syndrome and 17 other CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sézary syndrome including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, CREBBP, MLL2, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NFκB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sézary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

“…Interestingly, some of the TCR-related genes may be altered through point mutations or small indels as well as by major structural rearrangements, amplifications, and deletions. 20,23,24 Collectively, these findings strongly suggest that genetic alterations affecting TCR signaling operate as a common pathogenic mechanism in several PTCL entities.…”

“…Ten different missense mutations spanning the coding region of PLCG1 (VF [2.1%; 38%]) were identified in 12 of 85 patients (8 AITL, 4 TFH-like PTCL; 14.1%) ( Figure 5A). Apart from previously reported variants in adult T-cell leukemia/lymphoma (ATLL) or in other PTCL, [20][21][22][23][24] we identified 2 novel variants (E730K and G869E). We generated all mutant constructs and tested their activity against WT PLCG1 in a FRET-based reporter assay of MALT1 protease activity 27,28 (Figure 5B) and in a NFAT luciferase reporter assay ( Figure 5C).…”

“…[20][21][22][23][24]53 Nonetheless, mutations in specific genes are variably recurrent in distinct entites, 24,25 and for a given gene, the distribution of the mutations and their relative prevalence are G869E E730K S520F S345F D1165G D1165H E1163K D342G R48W E47K PH1 PI heterogeneous. For instance, PLCG1 and CARD11 mutations are highly prevalent (up to 18% and 15% of the cases, respectively) in cutaneous T-cell lymphoma, in which conversely CD28 mutations are not found.…”

“…19 Mutations or gene fusions in costimulatory/TCR signaling genes as CD28, FYN, PLCG1, or CARD11 have also been reported in several PTCLs. 12,[20][21][22][23][24][25] However, alterations in the TCR signaling pathway have not yet been extensively studied in TFH-related lymphomas. Here, we focused on investigating mutations in the costimulatory/TCR signaling cascade in a series of AITL and TFHlike PTCLs using a targeted deep-sequencing approach.…”

Expanding and expounding the genomic map of CTCL

“…[2][3][4][5][6][7][8] These studies have now confirmed, expanded, and functionally validated many of the genetic aberrations detected by aCGH in MF/SS, a broad and diverse spectrum that include genes associated with T-cell receptor (TCR) signaling, activation of NF-kB, JAK/STAT signaling, chromatin remodeling, and DNA damage response. However, despite a significant degree of overlap, there was great variability in the identity and frequency of alterations at putative driver genes across studies.…”