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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+ T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sézary syndrome and 17 patients with other CTCLs. These analyses identified 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, KMT2D (MLL2), KMT2C (MLL3), BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NF-kB 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.
Mycosis fungoides and Sézary syndrome are primary cutaneous T cell malignancies derived from CD4+ skin-homing T cells1,2. Mycosis fungoides cases with limited skin involvement have a favorable prognosis; however, the median survival time for cases with cutaneous tumors and generalized erythroderma is approximately 4 years, and patients with Sézary syndrome fare even worse, with survival times of about 2 years (refs. 2,3).
To investigate the genetic mechanisms of aggressive CTCLs, we performed whole-exome sequencing of 42 CTCL cases, including 25 Sézary syndrome cases and eight mycosis fungoides cases (Supplementary Table 1). For each sample, we generated an average of 115 million reads, resulting in an average coverage of 99.91% with over 95.3% of targeted regions showing >30× coverage (Supplementary Table 2).
In agreement with previous studies4-8, copy number analysis from exome data identified a median of 21 copy number alterations per sample (range of 0-56) in Sézary syndrome, with characteristic recurrent gains in chromosome 7 (5/25, 20%), 8q (13/25, 52%) and 17q (2/25, 8%), as well as recurrent deletions involving tumor- suppressor genes in 17p13.1 (TP53; 13/25, 52%), 13q14.2 (RB1; 4/25, 16%), 10q23.3 (PTEN, 5/25; 20%) and 12p13.1 (CDKN1B; 5/25, 20%) (Fig. 1 and Supplementary Table 3). Focal chromosome 2p23.3 deletions encompassing the DNMT3A locus were observed in five patients with Sézary syndrome (5/25, 20%), including two cases...