A Forward Genetic Screening for Prostate Cancer Progression Genes

Exome sequencing has revealed that somatic mutations in human melanomas greatly exceed those in other cancers, making it a challenge for predicting causative genes from the large collection of mutations. Here we used low‐copy piggyBac (PB) transposon mutagenesis in mice with conditionally activated Braf in melanocytes to screen for genes promoting melanoma development. Analysis of eleven PB‐induced melanomas revealed on average four mutated genes per tumor, circumventing the problem of high background mutations. The two bona fide melanoma drivers relevant to patients with oncogenic BRAF mutations, CDKN2A and MITF, were identified, demonstrating the validity and efficiency of the screen. Notably, analysis of the identified genes in conjunction with human melanoma mutational data revealed two recurrently mutated networks involving MAGI2 and MAP3K1/2, and disruption of MAGI2 can transform human melanocytes. Overall, 34 out of 38 identified genes are mutated in human melanomas, providing invaluable instructive information for sorting through the large collection of mutations and differentiating genes important for melanomas. In summary, low‐copy transposon mutagenesis in mice offers a powerful and complementary way to decipher relevant alterations for human conditions, especially those accompanied by high degrees of