biostudies-literatureNi TKHoward Hughes Medical InstituteNHGRI NIH HHSNIGMS NIH HHSE3640-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC3780872biostudies-literatureUnknown110(38)Despite considerable efforts to sequence hypermutated cancers such as melanoma, distinguishing cancer-driving genes from thousands of recurrently mutated genes remains a significant challenge. To circumvent the problematic background mutation rates and identify new melanoma driver genes, we carried out a low-copy piggyBac transposon mutagenesis screen in mice. We induced eleven melanomas with mutation burdens that were 100-fold lower relative to human melanomas. Thirty-eight implicated genes, including two known drivers of human melanoma, were classified into three groups based on high, low, or background-level mutation frequencies in human melanomas, and we further explored the functional significance of genes in each group. For two genes overlooked by prevailing discovery methods, we fouProceedings of the National Academy of Sciences of the United States of AmericaLow-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma.PMC3780872T32 GM007499T32 HG003198Landrette SFBosenberg MWNi TKXu TBjornson RDfalseLow-copy piggyBac transposon mutagenesis in mice identifies genes driving melanoma.Despite considerable efforts to sequence hypermutated cancers such as melanoma, distinguishing cancer-driving genes from thousands of recurrently mutated genes remains a significant challenge. To circumvent the problematic background mutation rates and identify new melanoma driver genes, we carried out a low-copy piggyBac transposon mutagenesis screen in mice. We induced eleven melanomas with mutation burdens that were 100-fold lower relative to human melanomas. Thirty-eight implicated genes, including two known drivers of human melanoma, were classified into three groups based on high, low, or background-level mutation frequencies in human melanomas, and we further explored the functional significance of genes in each group. For two genes overlooked by prevailing discovery methods, we fou2013-01-01T00:00:00Z2013 Sep2026-04-13T17:59:34.747Z2026-04-07T13:36:26.178ZS-EPMC37808722400313110.1073/pnas.1314435110