Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a ‘loss of heterozygosity’ deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes. The loss of the TP53 gene is often involved in the development of human cancer; here, the deletion of other genes in the vicinity is shown also to contribute to cancer progression in a mouse model. Loss of the human tumour suppressor gene TP53 is a frequently a two-step process involving a point mutation in one allele and a chromosomal deletion event in the other. These events clearly inactivate p53, and in this study Scott Lowe and colleagues demonstrate in a mouse model that the deletion of genes other than Trp53 also contributes to cancer progression in a mouse model. Genomic analysis and gene expression profiling suggest that the tumorigenic effects of the chromosome 17p deletion reflect the combined effect of TP53 loss and the reduced dosage of linked tumour suppressor genes.