We are developing a project to investigate the functional consequences of RIT1 alterations in uterine carcinosarcoma. The Cancer Genome Atlas (TCGA) found that somatic copy number alterations (gains and losses) are common in uterine carcinosarcomas and include a chromosome 1q22 amplification encompassing the RIT1 gene. A detailed query of TCGA's uterine cancer datasets shows that RIT1 is amplified in 14% of uterine carcinosarcomas, 22% of serous endometrial carcinomas (ECs), and 4% of endometrioid ECs. By extending the query to include somatic mutations and dysregulated gene expression, the incidence of RIT1 genomic alterations increases to 39% in uterine carcinosarcoma, 26% in serous EC, and 27% in endometrioid EC, with most of the additional cases being attributed to mRNA upregulation; in uterine carcinosarcomas RIT1 amplification was almost always accompanied by RIT1 mRNA upregulation. The RIT1 (Ras like without CAAX-1) small GTPase is a component of the RAS-MAPK pathway. Evidence supporting RIT1 as a cancer gene comes primarily from studies in lung cancer in which oncogenic (gain-of-function) RIT1 mutations have been found in a subset of tumors. Here, we hypothesize that amplification and/or overexpression of the RIT1 gene is oncogenic in uterine carcinosarcoma.
