Background: According to the IARC, lung cancer is one of the most common types of cancer worldwide (2.09 million of cases in 2018). Some genetic alterations (ALK, ROS1, EGFR, etc.) are known to play a key role in its origin. Fortunately, target therapies have been developed in the last years increasing patients Overall Survival (OS). Methods: Next-Generation Sequencing (NGS) is a powerful tool to determine which specific mutations occur in these genes. Nevertheless, despite some of them have been labeled as pathogenic, we still do not know exactly their effect on the OS. In this context, we have evaluated the NGS (Ion Torrent™ S5, kit Oncomine™ Focus Assay, Oncomine Focus-520- W3.0-DNA v5.14) results of 119 patients diagnosed with lung adenocarcinoma (89 variants in 28 genes) with a cross-validated (k = 5) schema using Partial Least Squares (PLS) and multiple repetitions to determine the coefficient variability from the genetic alterations modeling the OS. This gives us a measure of the proportion of variance in the OS (dependent variable) that is explained by the mutations (independent variables) in our statistical model. Results: Analyzing our results, alterations on ALK EML4-ALK V1 (CI -58.7 to -18.8); BRAF SNV exon15 p.Val600Glu (CI -66.1 to 0.0); CTNNB1 SNV exon3 p.Thr41Ala (CI -84.3 to 8.8) and p.Thr41Ile (CI -26.0 to 0.6); EGFR CNV (CI -68.5 to -5.1) and DEL exon19 p.Glu746-Ala750 (CI -66.9 to 16.4); KRAS SNV exon2 p.Gly12Val (CI -76.1 to -39.3) and p.Gly13Cys (CI -66.0 to -36,9); MET CNV (CI -50.0 to 1.3) and FUS exon13 to exon15 (CI -46.8 to 33.6); and PIK3CA SNV exon10 p.Glu545Lys (CI -99.0 to -35.6) have a negative impact on the OS. In contrast, mutations in CTNNB1 SNV exon3 p.Ser37Phe (CI -26.3 to 105.5); EGFR SNV exon21 p.Leu858Arg (CI -32.7 to 121.3); KRAS SNV exon2 p.Gly12Ala (CI 1.3 to 39.3); KRAS SNV exon3 p.Gln61His (CI -53.32,50,11) lead to a better prognosis on OS. Note that our analysis involved patients not treated due to their tumoral progression: CTNNB1 SNV exon3 p.Thr41Ile (1); EGFR SNV exon21 p.Leu858Arg (3); CTNNB1 SNV exon3 p.Thr41Ala (1); PIK3CA SNV exon10 p.Glu545Lys (1); ALK EML4-ALK V1 (1) and KRAS SNV exon2 p.Gly12Val (1). Conclusions: Though alterations in the EGFR and ALK genes usually present a favorable prognosis, our work suggests that some of their variants are associated with a poor survival. This study also reveals other mutations like alterations on PIK3CA and CTNNB1 genes, which may impact lung cancer prognosis and will require further exploration.