PO-341 Functional role of APOBECS in upper aerodigestive tract tumours

Abstract

IntroductionThe AID/APOBEC family consists of proteins that participate in a process known as DNA editing. APOBEC signatures are present in many tumour genomes as C-to-T and as C-to-G in TpC context. In esophageal squamous cell carcinoma (ESCC), an APOBEC-mediated mutational signature in 50% of tumour samples suggests that APOBEC-catalysed deamination provides a source of DNA damage. Head and neck squamous cell carcinoma (HNSCC) also shows high APOBEC3B mRNA levels and display the putative APOBEC mutational signature. HNSCC and esophageal cancer are the 5th and 6th most frequent types of cancer, respectively, in Brazil among men. HNSCC and ESCC are tumours with similarities in morphology and etiologic factors. Based on these findings, this study was designed to evaluate the contribution of APOBECs to the mutational signature of HNSCC and ESCC.Material and methodsMutational and gene expression profile were evaluated by RNA-seq in samples from INCA. Further validation was performed by RT-qPCR. Furthermore, data regarding exome sequencing and RNA-seq were also obtained from TCGA database. Bioinformatics analyses were performed using R software. All differences were considered statistically significant when p<0.05.Results and discussionsThrough the exome sequencing data from TCGA of HNSCC and ESCC samples, we observed that the predominant mutational signature these tumours was of APOBEC signature followed by tobacco signature, except for larynx cancer (LSCC). So, we focused on ESCC and LSCC analyses. Using RNAseq, APOBEC3A, APOBEC3B, APOBEC3D, APOBEC3F, APOBEC3G and APOBEC3H were found overexpressed in tumour when compared with matched surrounding non-tumour mucosa of 14 ESCC patients. Furthermore, in 8 LSCC patients, the same APOBECs, aside from APOBEC3H, were found overexpressed in tumour when compared with matched surrounding non-tumour mucosa. Besides, the mutation fractions of C-to-G and C-to-T in TpC context were lower in LSCC than in ESCC samples. We also observed a positive correlation between APOBEC3H expression with total APOBEC mutations (r2: 0.347, p value: 0.027); with C-to-T APOBEC mutations (r2: 0.380, p value: 0.019); and between APOBEC3D expression and total APOBEC mutations (r2: 0.326, p value: 0.033); with C-to-T APOBEC mutations (r2: 0.298, p value: 0.043) and with C-to-G APOBEC mutations (r2: 0.294, p value: 0.045) in ESCC patients.ConclusionThe deregulation of the APOBEC family of genes is a common feature in ESCC and LSCC, but the APOBEC signature seems to be able to distinguish these two tumours.