Abstract 178: Desmosome mutations in melanoma promote cellular proliferation and disease progression

Abstract Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in the epithelia and other tissues under mechanical stress. Aberrant desmosome expression is often associated with developmental diseases leading to impaired tissue integrity. Recently, similar findings have been reported in cancer; Mutations in desmosomes genes have been observed in various cancer types including skin cancer, head and neck and lung cancer, however mostly epigenetic alterations have been used to associate desmosomes as suppressors of tumor metastasis. Here, we report that desmosomes are frequently mutated in seven cancer types. In melanoma, we find that over 70% of tumors have non-synonymous mutations in desmosomes, and that the desmosome mutational burden is associated with a strong decrease in mRNA expression levels in primary tumor samples (R = -0.23). Differential gene expression analysis and functional characterizations between mutant and wild-type tumors implicates the mutated cells in promoting cell proliferation at early stages of tumorigenesis. These results emerge uniquely from a systems-level analysis integrating multiple proteins in complexes and multiple cell types in heterogeneous tumors. Citation Format: Maayan Baron, Trey Ideker. Desmosome mutations in melanoma promote cellular proliferation and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 178.