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Nat Genet. 2015 Dec;47(12):1465-70. doi: 10.1038/ng.3442. Epub 2015 Nov 9.

The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.

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  • 1Institute for Cancer Genetics, Columbia University, New York, New York, USA.
  • 2Department of Biomedical Informatics, Columbia University, New York, New York, USA.
  • 3Department of Dermatopathology, Northwestern Medical Faculty Foundation, Chicago, Illinois, USA.
  • 4Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
  • 5Department of Systems Biology, Columbia University, New York, New York, USA.
  • 6Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
  • 7Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.


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.

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