Recurrent Novel Regions of Uniparental Disomy and Homozygous Deletions in Mycosis Fungoides Identified Using High Resolution Single Nucleotide Polymorphism Analysis.
Authors: Mohamedali Azim M , Mitchell Tracey J , Ferreira Silvia , Guinn Barbara A , Ireland Robin M. , Whittaker Sean J , Mufti Ghulam J 
Published: October 2019

Abstract
Abstract 2644
Poster Board II-620
Mycosis Fungoides (MF) is the commonest form of primary cutaneous T-cell lymphoma but our understanding of the underlying molecular pathogenesis remains limited. Cytogenetic studies remain limited due to difficulties in obtaining analysable mitotic chromosomes for metaphase G-band analysis from MF patients. We have utilised high resolution 250k Affymetrix single nucleotide polymorphism (SNP) arrays to analyse tumour samples from 34 MF patients including 12 paired skin samples using and identified 156 chromosomal aberrations in ten patients (29%). Compared with previous studies using comparative genomic hybridization (CGH) in both MF and Sezary syndrome (SS), SNP array analysis detected a greater frequency of deletions and amplifications on chromosomes 1, 2, 3, 4, 5, 6, 11, and 16. Heterozygous deletions of chromosome 8 were also detected in 3 patients which have been undetected by CGH studies. A particular feature of SNP array technology is the detection of uniparental disomy (UPD) which are copy neutral regions of homozygosity. UPD (median size 32.3Mb (range: 6.6Mb – 159Mb)) was detected in 21% of our MF patients affecting either chromosome 7 (whole chromosome), 8p, 9p/9q, 10q, 12p, 14q, 16p/16q, 17q and 19q. Of note, two patients shared a common UPD region on chromosome 9p that specifically encompassed the p14 and p16 tumour suppressor genes. Thirteen regions of homozygous deletions were also observed in six patients (18%) on chromosomes 1p21.1, 7q34, 9p22.1-21.3, 10p12.1/p12.2/p14/q23.31/q23.1 and 16q23.1-q23.2. Common minimal homozygously deleted regions at 9p21-p22.3 and 16q23.1, suggest the presence of tumour suppressor gene in these regions. Interestingly, all the homozygous regions appeared within a larger region of the UPD or heterozygous deletion. Grouping patients with UPD/deletions or UPD/amplification identified eleven common minimal regions of genomic aberrations occurring in at least 3 patients; 3p24.1-14.2, 7p22.3-12.2, 7q31.1-31.2, 9p21.3-22.1, 10q21.2-26.13, 12p13.33-13.31, 13q14.2-21.1, 16p13.13, 16q23.1, 17p13.3-13.1 and 17q21.32-25.1. The detection of these recurrent abnormalities associated with UPD suggests a series of candidate genes selected for dysregulation through mutational or epigenetic modulation such as MLH, CDKN2A/B, RB1 and TP53. Paired plaque samples were also analysed from 12 patients. Of note, SNP analysis did not always show identical aberrations between these samples. Six patients had multiple aberrant regions in at least one of their samples. Of these, three patients had unique aberrations which were present in only one. This discordance in the distribution of genomic aberrations between the samples may reflect clonal evolution of the disease. To our knowledge, this is the first high resolution SNP array study in MF that has provided additional insight into the pathogenesis of MF. We have identified distinct aberrations not detected by previous studies as well as frequent and widespread UPD harbouring important oncogenes and tumour suppressor genes likely to play key roles in the dysregulation of MF cells.

Disclosures:
No relevant conflicts of interest to declare.