Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

Abstract

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

Transmicron: accurate prediction of insertion probabilities improves detection of cancer driver genes from transposon mutagenesis screens

“…To assess the generalizability of our models, we repeated this analysis in multiple previously described datasets ( 23 , 25 , 37 , 46 ) as well as the tail samples generated in our DLBCL experiments, which serve as negative, unselected controls. Overall, we found the predictive power of the various individual features to be similar between datasets ( Supplementary Figure S2A and B ), with some noticeable exceptions.…”

“…In addition to our newly generated DLBCL dataset, we analysed other datasets described in previous publications. Specifically, we examined screens from cohorts developing acute myeloid leukaemia (AML), cutaneous squamous cell carcinoma (cuSCC), hepatocellular carcinoma (HCC), and gastrointestinal tumours (Intestinal) ( 23 , 25 , 46 ), as well as insertions in mouse embryonic stem cells (mESC) ( 37 ). If insertion sites in these datasets had been mapped to the mm9 version of the mouse genome, a lift-over to mm10 was performed using the UCSC chain file.…”

Molecular Alterations in Cutaneous Squamous Cell Carcinoma in Immunocompetent and Immunosuppressed Hosts—A Systematic Review

“…Using whole-genome sequencing, Thind et al demonstrated significant recurrent copy number loss in the tumor suppressor genes KANSL1 and PTPRD [ 16 ]. Likewise, KMT2C , CREBBP , and NCOA2 were identified to demonstrate tumor-suppressive roles in the initiation and progression of human cSCC [ 17 ].…”

“…Aiderus et al defined two mutually exclusive paralogous oncogenic drivers, Zmiz1 and Zmiz2 , among the most recurrent drivers of cSCC development. Interestingly, all cSCC tumors with Zmiz1/2 insertions had inactivating insertions in at least one gene involved in chromatin remodeling, suggesting that alterations in epigenetic regulation are essential in cSCC development [ 17 ]. Actin-like protein 6A ( ACTL6A , BAF53a ) is a key protein subunit of the SWI/SNF epigenetic chromatin regulatory complex.…”

Fusion‐driven cutaneous and superficial mesenchymal and adnexal tumors—A clinicopathologic and molecular study of 15 cases, including a novel case of ACTB::ZMIZ2‐rearranged adnexal carcinoma

“…Equally, the role of ZMIZ2 as a fusion partner remains poorly understood, however, some data is suggesting its importance as an oncogenic driver in cutaneous squamous cell carcinoma. 39 ZMIZ2 is a member of the protein inhibitor of the activated STAT-like family and interacts with nuclear hormone receptors such as AR (Huang et al…”