Background: Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer with low survival rates. NSCLC patients harboring EGFR mutations are benefited by targeted therapy with tyrosine kinase inhibitors. The mutational profiling and the knowledge about recurrent mutations in Brazilian NSCLC is limited. Therefore, the detection of the mutation landscape of Brazilian NSCLC tumors is crucial for tailored therapy. Aim: To evaluate the mutational profiling of NSCLC of a Brazilian series.

Methods: We analyzed a series of 40 NSCLC patients from Barretos Cancer Hospital. Clinical staging and exposure data were collected from all patients. Exome sequencing was performed in paired tumor/blood tissue DNA using the Illumina HiSeq2500™ System. Germline variations were excluded and the Genome Analysis Toolkit and VarScan were used for variants annotation and mutation detection.

Results: Overall, 29 (72.5%) of cases were adenocarcinomas and 11 (27.5%) were squamous cell carcinoma (SCC) and the series was enriched by initial stages cases (I, n=16; II, n=12; III, n=6; IV, n=6). Regarding tobacco exposure, 33 patients were current smokers or former smokers and 7 patients were never smokers. In accordance, most of the cases presented the mutation signature 4, related to tobacco exposure, which is characterized by C>A substitutions and signature 29, related to tobacco chewing habit, which is characterized by C>A and C>T substitutions. All SCC patients were current or former smokers. TP53 gene was the most recurrently mutated gene observed in 48% (n=14) of the adenocarcinomas and 100% (n=11) of SCC cases (p=0,003). In adenocarcinomas, besides of TP53 gene, recurrent mutations were also found in KRAS (28%; n=8), STK11(21%; n=6), USP36 and APOB (14%; n=4/each), POLQ and CHD5 (10% n=3/each), EGFR and ANO3 (7%; n=2/each) and PDGFRA, BRAF, ERBB2, ERBB4, NRAS, RB1, CD22, CTNNA2 and ATR mutations were identified in only one adenocarcinoma case (3%). In SCC, besides of TP53 gene, recurrent mutations were also found in RB1, CD22, CTNNA2 and CHD7 (27%; n=3/each), ATR and APOB (18%; n=2/each), KRAS, PDGFRA, ERBB2, ERBB4, POLQ, CHD5 and ANO3 were identified in only one SCC case (9%). EGFR, STK11, BRAF, NRAS and USP36 mutations were exclusively found in adenocarcinomas and CHD7 mutations were exclusively found in SCC.

Conclusions: The mutational landscape of lung adenocarcinoma and SCC are clearly different. A noteworthy number of pathogenic mutations was identified in this initial stages-enriched series. Our results may contribute to improve the knowledge about the molecular pathogenesis of NSCLC to better guide the clinical management with targeted therapies.

Citation Format: Leticia Ferro Leal, Adriane Feijo Evangelista, Pedro R. de Marchi, Ysadhora Christiane Camargo Rodrigues, Eduardo Caetano Albino da Silva, Rui Manuel Reis. Whole-exome sequencing of Brazilian non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5380.