Type II Rothmund-Thomson syndrome (Type II RTS) is a rare autosomal recessive genetic disorder characterized by a congenital skin rash, birth defects of the skeleton, genomic instability and cancer predisposition. It is caused by mutations in the RECQL4 gene and thus represents one of the three cancer-prone genetic diseases that are caused by mutations in a RecQ helicase-encoding gene. Genomic instability has been suspected as a major underlying cause of this disease, and analyses of Type II RTS patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations, suggesting the involvement of chromosomal instability. However, the nature of the instability induced by RECQL4 mutations has not been clearly defined. We created a viable Recql4 mutant mouse model. These mice exhibit a distinctive skin abnormality, birth defects of the skeletal system, genomic instability and increased cancer susceptibility in a sensitized genetic background. Thus, they provide a useful model for studying Type II RTS. In addition, we demonstrate that cells from these mutant mice have high frequencies of premature centromere separation and aneuploidy. Thus, our observations provide evidence for a previously unsuspected role for Recql4 in sister-chromatid cohesion, and suggest that the chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.

To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) transposon mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

Although nearly half of human melanomas harbor oncogenic BRAFV600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in BrafV600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAFV600E melanoma and discover new genes with potential clinical importance in human melanoma.