Interestingly, functional overlap between subtype
specific signatures has been observed, suggesting disruption INCB024360 of specific pathways is selected for rather than specific genes. Deregulation of antioxidant proteins, detoxification genes and overexpression of cytokeratins and cytokeratin-regulatory genes (GSTT1, CEL, and PRDX6) often characterize SqCC tumors , , ,  and , whereas disruption of surfactant-related and small airway-associated genes (SFTPA2, SFTPB, MUC1, and NAPSA) are typically altered in AC , , , ,  and . These functions are largely associated with the histological properties of the cells or origin from which these subtypes develop, Protein Tyrosine Kinase inhibitor further highlighting the contribution of histology to tumorigenesis. DNA copy number alterations (CNAs) are a prominent mechanism of gene disruption in NSCLC , , , , , , , , ,  and . Although very few CNAs are altered exclusively in a single subtype, many regions are altered
at significantly different frequencies between subtypes and therefore deemed regions of subtype specific CNA (Fig. 2A and Table 1) ,  and . For example, a recent analysis of over 2000 tumors identified 13 subtype-specific regions with at least a 25% difference in the frequency of alteration between subtypes . Amidst all copy number studies, the most prominent and consistent difference between subtypes is amplification of 3q in SqCC (Fig. 2A) , , , , , ,  and . Advances in exome
and whole genome sequencing technologies have enabled high throughput identification of mutations, copy number aberrations, and structural alterations such Adenosine as gene fusions and chromosomal rearrangements in a genome-wide, unbiased manner. One of the first high throughput sequencing studies of lung cancer interrogated 623 cancer related genes in 188 AC samples and identified over 1000 somatic mutations and 26 frequently mutated genes. These included genes known to be frequently mutated in lung cancer such as TP53, BRAF, ERBB2, KRAS, STK11, EGFR, PIK3CA, PTEN and CDKNA, in addition to NF1, RB1, ATM, FGFR4, and ERBB4 which had no previous evidence of recurrent mutation in lung cancer . Since then, sequencing of AC and matched non malignant tissue has continued to identify novel mutations and gene fusions (including ARID1A, SMARA4, ASH1L, U2AF1 and KIF5B-RET) while simultaneously revealing immense mutational heterogeneity both within (intra) and between (inter) patients , ,  and . For example, a single AC tumor was found to have over 50,000 variants, of which 391 affected coding sequences .