LB761 An integrated analysis of genomic datasets identifies recurrent mutations and altered pathways in cutaneous T-cell lymphoma

Abstract

The purpose of this study is to identify genes and molecular pathways that are commonly mutated in cutaneous T-cell lymphoma (CTCL). Recent studies have used whole genome or whole exome sequencing of CTCL samples to identify recurrently mutated genes. However, these studies usually include tumors of multiple types and stages. Thus, due to the genomic heterogeneity of CTCL, discovering genes or pathways that play a central role in CTCL pathogenesis remains challenging. Here, we combined and co-analyzed recently published genomic sequencing datasets of cutaneous T cell lymphoma. We generated a list of 6653 single nucleotide mutations in CTCL samples, including 67 Sezary syndrome and 19 mycosis fungoides. We found 19 recurrently mutated loci, including those for R48W in PLCG1, Q575E in RLTPR and a nonsense mutation of Y331 in CCR4. When the list of mutations is used to study commonly mutated genes, we found previously reported genes as well as genes that were not deemed significantly mutated by individual studies. Among the most frequently mutated genes are PCLO (20%), TP53 (16%) and FAT3 (16%). Sucrase-isomaltase (SI) a commonly mutated genes in CLL, is also identified. When mutations were analyzed in the context of biological pathways, we found genes in the T cell receptor pathway and the JAK/STAT pathway are frequently mutated in Sezary syndrome, including TNFR2 (8%), PLCG1 (11%) and CARD11 (11%). To conclude, by integrating multiple genomic sequencing datasets and increasing statistical power, we validated previous reported recurrent mutations in CTCL and identified additional genes that are frequently mutated. These results provide new information on the molecular mechanism of CTCL pathogenesis.