Despite the fact that lung cancer is the leading cause of cancer mortality worldwide, few genetic defects have been found to mediate its pathogenesis. Using a combination of high-resolution comparative genome hybridization (CGH) and gene-expression profiling, Ron DePinho and colleagues have now identified several loci with candidate oncogenes.

Non-small-cell lung cancer (NSCLC) accounts for over 75% of lung cancer cases, with adenocarcinoma and squamous cell carcinoma (SCC) being the most common subtypes. DePinho and colleagues attempted to define the genetic basis of these tumour types by first identifying regions of recurring chromosome gain and loss in tumour samples, and then associating these chromosomal aberrations with copy-number driven alterations in gene expression.

In comparing tumour subtypes of 44 NSCLC samples, they found that the chromosome region 3q26–29 was the only copy number alteration specific to the SCC subtype. This locus had also previously been reported to be amplified in SCC of the head and neck. So what genes in this region might contribute to SCC pathogenesis? The authors observed that p63, a known regulator of squamous cell differentiation, is at this locus and is overexpressed only in SCC samples. Mice that overexpress this gene develop severe squamous metaplasia, so p63 is a good candidate for an SCC oncogene.

Other than the amplification of the chromosome-3 region, there were no major differences observed between the NSCLC subtypes, indicating that adenocarcinomas and SCCs might arise from a common lung stem cell or precursor cell. DePinho also compared the NSCLC dataset with other recently published CGH datasets, and found that two amplicons, at 8p12 and 20q11, were common to both NSCLC and pancreatic ductal adenocarcinoma. Genes in these regions that were amplified and overexpressed in tumour samples included WHSC1L1, which had been previously observed to be amplified in breast cancer, and TPX2, which regulates Aurora A function at the spindle checkpoint. This technology has therefore yielded important new candidates for the genetic basis of lung cancers.