Figure 2. Spectrum of major co-occurring genomic alterations in KRAS- and EGFR-mutant lung adenocarcinoma.

Volcano plots (left graphs) summarizing enrichment of individual co-alterations in: KRAS-mutant compared with KRAS-wild-type LUADs (a) and EGFR-mutant compared with EGFR-wild-type LUADs (b). The magnitude of co-mutation enrichment is indicated on the x-axis and is expressed as log₂ (% in KRAS-mutant / % in KRAS-wild-type) or log₂ (% in EGFR-mutant / % in EGFR-wild-type) respectively, whereas the statistical significance of the association is plotted on the y-axis and is expressed as –log₁₀P value (derived from a Fisher’s exact test). Significantly enriched co-mutations based on a q value <0.05 (derived from Benjamini-Hochberg procedure¹⁸²) are highlighted in red, whereas under-represented genomic events are highlighted in blue. The prevalence of each co-alteration in KRAS-mutant and KRAS-wild-type groups (or EGFR-mutant and EGFR-wild-type groups) is shown in the adjacent frequency plots (right graphs of parts a and b). Targeted next generation sequencing-based molecular profiling (MSK-IMPACT platform) from 860 patients with metastatic LUAD treated at Memorial Sloan Kettering Cancer Center were included in this enrichment analysis that was performed using the cBioPortal web program^{180, 181}. Oncogene-driver specific, non-random patterns of co-occurring alterations in key tumor suppressor genes are evident for both KRAS-mutant and EGFR-mutant tumors.