# Comprehensive genomic characterization of squamous cell lung cancers

Source: https://onco.cc/key-papers/paper-tcga-lung-squamous-nature-2012/  
OnCo record `paper-tcga-lung-squamous-nature-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Nature
- Year: 2012
- DOI: 10.1038/nature11404
- Authors: Cancer Genome Atlas Research Network.
- Findings: TP53 mutated in nearly all specimens; a mean of 360 exonic mutations and 323 copy-number segments per tumour.; NFE2L2 and KEAP1 pathway altered in 34%, squamous differentiation genes in 44%, PI3K pathway in 47%, CDKN2A and RB1 in 72%.; Loss-of-function mutations in HLA-A, a route to immune escape.; A candidate therapeutic target present in most tumours.
- What it means: 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.
- Caveats: The candidate targets identified here, including FGFR1 and the PI3K pathway, have largely failed in trials since.; A resected cohort, so stage IV biology is not represented.; 178 tumours, so rarer events are missed.

## Sources

- Cancer Genome Atlas Research Network, Nature 2012: comprehensive genomic characterisation of 178 squamous cell lung cancers: https://doi.org/10.1038/nature11404
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22960745/
- cBioPortal study lusc_tcga_pub (TCGA, Nature 2012; the 178 squamous cell lung cancers of the landmark paper): https://www.cbioportal.org/study/summary?id=lusc_tcga_pub

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [CDKN2A](https://onco.cc/targets/cdkn2a/), [CUL3](https://onco.cc/targets/cul3/), [FGFR1](https://onco.cc/targets/fgfr1/), [HLA-A](https://onco.cc/targets/hla-a/), [KEAP1](https://onco.cc/targets/keap1/), [NFE2L2](https://onco.cc/targets/nfe2l2/), [NOTCH1](https://onco.cc/targets/notch1/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [PTEN](https://onco.cc/targets/pten/), [RB1](https://onco.cc/targets/rb1/), [SOX2](https://onco.cc/targets/sox2/), [TP53](https://onco.cc/targets/tp53/), [TP63](https://onco.cc/targets/tp63/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [KEAP1-NRF2 antioxidant pathway](https://onco.cc/pathways/keap1-nrf2/), [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/)
- terms: [Copy number alteration (CNA)](https://onco.cc/terms/copy-number-variation-term/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/)
- journals: [Nature](https://onco.cc/journals/nature/)

---
JSON: https://onco.cc/api/v1/entities/paper-tcga-lung-squamous-nature-2012.json