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The first complete genomic reading of 178 squamous lung cancers found a chaotic genome with almost universal loss of the p53 gene, and identified a possible drug target in most tumours in a cancer that until then had none.
One hundred and seventy-eight lung squamous cell carcinomas were profiled across platforms. The tumour type is characterised by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements and 323 segments of copy-number alteration per tumour. Recurrent mutations were found in 11 genes, including TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the class I gene HLA-A. Significantly altered pathways included NFE2L2 and KEAP1 in 34% of tumours, squamous differentiation genes in 44%, phosphatidylinositol-3-kinase pathway genes in 47%, and CDKN2A and RB1 in 72%. A potential therapeutic target was identified in most tumours.
It explained why squamous lung cancer has no equivalent of an EGFR inhibitor: its commonest alterations are a transcription factor amplicon, a tumour suppressor deletion and an antioxidant switch, none of which is a drug target in the way a mutant kinase is.
Shares Copy number alteration (CNA), NOTCH1, PTEN, RB1.
Shares KEAP1-NRF2 antioxidant pathway, KEAP1, Broad Institute of MIT and Harvard, Non-small cell lung cancer (KEGG map).
Shares Copy number alteration (CNA), KEAP1, Non-small cell lung cancer (KEGG map), Driver mutation.
Shares PTEN, RB1, PIK3CA / PI3K-alpha, Nature.
Shares KEAP1-NRF2 antioxidant pathway, KEAP1, CDKN2A, PI3K / AKT / mTOR.
Shares Chromosomal instability & aneuploidy, Broad Institute of MIT and Harvard, PIK3CA / PI3K-alpha, Nature.
Shares NFE2L2, KEAP1-NRF2 antioxidant pathway, KEAP1, RB1.
Shares NOTCH1, RB1, Driver mutation, Nature.