Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome.
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.
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Wesley J
WJ
Woollard
BRC Bioinformatics Core, Tower Wing, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; and.
Venu
V
Pullabhatla
BRC Bioinformatics Core, Tower Wing, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; and.
Anna
A
Lorenc
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Varsha M
VM
Patel
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Rosie M
RM
Butler
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Anthony
A
Bayega
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Nelema
N
Begum
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Farrah
F
Bakr
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Kiran
K
Dedhia
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Joshua
J
Fisher
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Silvia
S
Aguilar-Duran
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Charlotte
C
Flanagan
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Aria A
AA
Ghasemi
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Ricarda M
RM
Hoffmann
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Nubia
N
Castillo-Mosquera
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Elisabeth A
EA
Nuttall
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Arisa
A
Paul
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Ceri A
CA
Roberts
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Emmanouil G
EG
Solomonidis
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Rebecca
R
Tarrant
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Antoinette
A
Yoxall
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Carl Z
CZ
Beyers
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Silvia
S
Ferreira
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Isabella
I
Tosi
Department of Genetics, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom.
Michael A
MA
Simpson
BRC Bioinformatics Core, Tower Wing, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; and.
Emanuele
E
de Rinaldis
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Tracey J
TJ
Mitchell
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Tower Wing, King's College London, London, United Kingdom;
Sean J
SJ
Whittaker
D002470:Cell Survival / Q000235:genetics; D004260:DNA Repair; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012751:Sezary Syndrome / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D009363:Neoplasm Proteins