966P - Mutation profiles of nasopharyngeal carcinomas in South-Eastern European patients

Abstract

Nasopharyngeal cancer (NPC) is characterized by a remarkable geographical variation and biologic diversity. Importantly, studies investigating mutation profiles of NPC in European populations are scarce. We investigated the mutational profile of 127 NPC (89% EBV positive) in 93 Greek (GR) and 34 Romanian (RO) patients with locally advanced disease, treated with concomitant chemo-radiotherapy (CCRT) or induction chemotherapy (IC) followed by CCRT. In 19 tumors, dissected matched tumor/lymphocyte (T/L) pairs were compared. Mutation (amino acid changing, minor allele frequency <0.1%; splice-site changing) data were obtained with next generation sequencing (mean depth 3261.5) with a panel targeting areas in 100 NPC, DNA repair, and immune response related genes. Disease-free survival at 3 years (3yrDFS) was the clinical endpoint. We identified 1562 mutations in 101/129 tumors (94%). Mutations were mostly found in homologous recombination repair (HRR; 34%), chromatin remodelling (15%) and immune response related (IRR; 10%) genes. In the matched T/L samples, common mutations were identified in 10 cases only, the rest harbouring private mutations. Shared T/L mutations occurred at higher frequencies within the same tumor than T- and L-private mutations (p < 0.001). HRR and tyrosine kinase signalling genes, as well as POLE and TP53 carried mostly L-private (p = 0.003). In comparison to GR, RO patients were younger (p = 0.027), had almost exclusively WHO type II and III tumors (p = 0.025) and presented more often with stage IV disease (p = 0.026), while their tumors had significantly higher mutation load (p < 0.001) and higher numbers of mutations in particular genes, e.g., BRCA1 (p < 0.001). Multivariate analysis revealed BRCA1 mutations (odds ratio [OR] 6.3; 95% CI 1.3-31.4; p = 0.024) and absence of EBV infection (OR: 6.2; 95% CI 1.1-35.9; p = 0.040) as unfavourable prognostic parameters. Different genes and sets of genes are affected in stromal and tumor components of NPC, which is important for targeted treatment considerations. Ethnic differences in mutation profiles exist but do not seem to interfere with patient outcome, which seems adversely affected by the absence of EBV and by the presence of BRCA1 mutations.