GENOMIC LANDSCAPE OF BRAZILIAN NON-SMALL CELL LUNG CANCER

Background: Non-Small Cell Lung Cancer (NSCLC) NSCLC patients may be benefited by tailored treatment based on genomic profiling. However, the genomic landscape of Brazilian NSCLC remains unknown. Aim: to evaluate the genomic profiling of Brazilian NSCLC. Methods: We analyzed 96 NSCLC patients from Barretos Cancer Hospital, Brazil. Exome sequencing from paired tumor/blood DNA was performed by Illumina HiSeq2500; VarScan was applied for germline alterations exclusion, variant calling and annotation. Cancer Genome Interpreter was employed for identification of driver genes, Somatic Signature for Mutational Signatures and Circular Binary Segmentation for Copy Number Variations (CNV). Gene expression profiling (GEP) was assessed by NanoString and pathway enrichment by KEGG. Results: Overall, 61 cases were adenocarcinomas, 34 squamous cell carcinomas and 1 was adenosquamous (I,n = 19; II,n = 14; III,n = 23; IV,n = 40); 82 patients were current/former smokers and most of them presented the mutational signature 4 (never smokers, n = 12). More than 30,000 mutations were detected and 733 were classified as drivers (known:90; predicted:643). TP53 gene was the most recurrently mutated gene (56%). Besides of TP53 gene, recurrent mutations were found in KRAS (23%), EGFR (12.5%), NFE2L2 (9%), HERC2 (9%), STK11, ROS1, PIK3CA and CDKN2A (8%). KRAS, EGFR, STK11 and ROS1 mutations were mutually exclusive. CNV gain was observed in 1q21.3, 1q22, 3q26, 31q29, 7q11.21, 7p11.1-q11.1, 8p11.1-q11.1, 19q13. Downregulation of DKK1, IBSP, LAMC2, NGFR and LAMB3 and upregulation of LAMC3, MAPK8IP1, IL5RA, NR4A1, AXIN2, PLA2G4E, COL6A6, LRP2, NR4A3, FOS, and FGFR2 were observed in early disease stages indicating enrichment of PI3K-Akt, MAPK, Ras, Rap1 and Wnt signaling pathways. Downregulation of MCM2, VEGFA, E2F1, HMGA1, CCNE1, CHEK1, RAD51, FOSL1, CCNB1, IL11 and IL8 and upregulation of WNT10B, MAPK10, WNT4, IL7R, PIK3CG, and FGFR2 were observed in never smokers indicating Cell cycle, Pathways in cancer and PI3K-Akt signaling enrichment. GEP of KRAS-mutated tumors mostly indicated ECM-receptor interaction enrichment and TP53-mutated tumors indicated cell cycle enrichment. Conclusions: The genomic profiling of Brazilian NSCLC indicated remarkable driver mutations and amplifications. GEP indicates the enrichment of key pathways enrolled in TP53- and KRAS-driven tumors. Our results may contribute for the knowledge of molecular pathogenesis of Brazilian NSCLC.