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The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome

2015; Nature Portfolio; Volume: 47; Issue: 12 Linguagem: Inglês

10.1038/ng.3442

1546-1718

Ana Carolina da Silva Almeida, Francesco Abate, Hossein Khiabanian, Estela Martínez-Escala, Joan Guitart, Cornelis P. Tensen, Maarten H. Vermeer, Raúl Rabadán, Adolfo A. Ferrando, Teresa Palomero,

CAR-T cell therapy research

Teresa Palomero, Adolfo Ferrando, Raul Rabadan and colleagues report the results of an exome sequencing study of cutaneous T cell lymphoma (CTCL). They identify highly recurrent chromosomal deletions along with a broad spectrum of somatic mutations in genes involved in epigenetic regulation and signaling. 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-κB 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.