Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Wesley J Woollard, Venu Pullabhatla, Anna Lorenc, Varsha M Patel, Rosie M Butler, Anthony Bayega, Nelema Begum, Farrah Bakr, Kiran Dedhia, Joshua Fisher, Silvia Aguilar-Duran, Charlotte Flanagan, Aria A Ghasemi, Ricarda M Hoffmann, Nubia Castillo-Mosquera, Elisabeth A Nuttall, Arisa Paul, Ceri A Roberts, Emmanouil G Solomonidis, Rebecca TarrantAntoinette Yoxall, Carl Z Beyers, Silvia Ferreira, Isabella Tosi, Michael A Simpson, Emanuele de Rinaldis, Tracey J Mitchell, Sean J Whittaker

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)


Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.

Original languageEnglish
Pages (from-to)3387-97
Number of pages11
Issue number26
Early online date27 Apr 2016
Publication statusPublished - 30 Jun 2016


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