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Endometrial polyps are common, localized overgrowths of endometrial glands and stroma that protrude into the uterine cavity. These tumor-like lesions can cause symptoms like abnormal uterine bleeding and infertility, and they may undergo malignant transformation. The etiology of endometrial polyps remains largely unknown.

Here, we conducted whole-genome sequencing and global gene expression profiling on 23 polyps. Major findings were validated with targeted DNA (Sanger sequencing) and protein (immunohistochemistry) level analyses. Sanger sequencing was also utilized to validate the observed novel alterations in an additional set of 54 polyp samples.

The most common alterations were chromosomal rearrangements affecting HMGA1 and HMGA2, identified in 74% (17/23) of the polyps. These rearrangements involved LRMDA, RAD51B, TRAF3IP2, and 7p15.2 as recurrent rearrangement partners. 3'RNA sequencing indicated corresponding overexpression of HMGA1 and HMGA2 as well as a downstream target PLAG1. Elevated protein level expression of HMGA1 and HMGA2 was further shown using immunohistochemistry. In addition to frequent HMGA1 and HMGA2 alterations, we found UBE2A as a novel candidate driver gene with highly specific recurrent mutations. We also identified recurrent low-allelic fraction mutations in well-established cancer genes KRAS, PIK3CA, PIK3R1, and PTEN.

Here, we have characterized the genomic landscape of endometrial polyps. We show that chromosomal alterations affecting HMGA1 and HMGA2 are a major underlying cause for polyp development. In addition, we present UBE2A as a novel candidate gene for human tumorigenesis. Our results contribute to a better understanding of endometrial polyp development and pave the way towards the development of targeted, non-invasive treatment options.