AbstractUterine adenosarcomas (UAs) are biphasic lesions composed of a malignant mesenchymal (ie stromal) component and an epithelial component. UAs are generally low‐grade and have a favourable prognosis, but may display sarcomatous overgrowth (SO), which is associated with a worse outcome. We hypothesized that, akin to breast fibroepithelial lesions, UAs are mesenchymal neoplasms in which clonal somatic genetic alterations are restricted to the mesenchymal component. To characterize the somatic genetic alterations in UAs and to test this hypothesis, we subjected 20 UAs to a combination of whole‐exome (n = 6), targeted capture (n = 13) massively parallel sequencing (MPS) and/or RNA sequencing (n = 6). Only three genes, FGFR2, KMT2C and DICER1, were recurrently mutated, all in 2/19 cases; however, 26% (5/19) and 21% (4/19) of UAs harboured MDM2/CDK4/HMGA2 and TERT gene amplification, respectively, and two cases harboured fusion genes involving NCOA family members. Using a combination of laser‐capture microdissection and in situ techniques, we demonstrated that the somatic genetic alterations detected by MPS were restricted to the mesenchymal component. Furthermore, mitochondrial DNA sequencing of microdissected samples revealed that epithelial and mesenchymal components of UAs were clonally unrelated. In conclusion, here we provide evidence that UAs are genetically heterogeneous lesions and mesenchymal neoplasms. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.