Deletions of chromosomes 3p and 1p are among the most frequently observed mutations in human lung cancer. However, the candidate genes in these regions that have been studied to date have not turned out to be tumour suppressors in mouse models. Now, Hollander et al. have shown that deletion of Xpc causes lung tumours in mice, and also that Gadd45a deletions promote tumour progression.

XPC and GADD45A are found in humans at 3p and 1p, respectively, and both are involved in nucleotide excision repair. XPC polymorphisms in humans have been linked to the risk of developing cancer, and loss-of-function mutations of XPC cause skin cancer in the context of xeroderma pigmentosum. On this basis, the researchers studied the incidence of lung cancer over 24 months in mice that were homozygous for either Xpc or Gadd45a, as well as double mutants and controls. Mice were killed when they became ill or at 24 months if they survived until then. Lung tumours were then counted and graded.

All the Xpc−/− mice developed lung adenomas, though few showed progression to adenocarcinoma. By contrast, the controls and the Gadd45a−/− mice showed no evidence of tumour formation. In the double mutant, most tumours progressed to adenocarcinomas. These results show that Xpc is a tumour suppressor but that its loss is not sufficient for progression. Gadd45a, on the other hand, is involved in preventing progression.

The researchers also looked for other factors that are known to correlate with lung cancer. Polymorphisms in other markers of susceptibility, such as Pas1 and the Par genes, did not correlate with the incidence of tumours in these mice. Also, the tumours did not show consistent mutation in KRas, which was thought to be a likely result of Xpc inactivation.

Studies of human lung cancers show that the markers that flank XPC on chromosome 3p are lost in most tumours. The markers flanking GADD45A on chromosome 1p, on the other hand, are only lost in some lung tumours but are also lost in many other tumour types.

Tobacco carcinogens are the main cause of lung cancer. The discovery of a lung-tumour-suppressor gene that might repair the DNA damage caused by tobacco carcinogens gives a fresh insight into the mechanisms of lung carcinogenesis.