Background: Gynecologic carcinosarcomas (GCS) are histologically defined as biphasic neoplasms composed of an intimate admixture of carcinomatous epithelial and sarcomatous malignant components. Although these tumors represent a small fraction of newly diagnosed uterine or ovarian cancers, they disproportionately contribute to the population of patients recurring and dying from disease. Due to their rarity and to their histological complexity, genetic and functional studies on GCS are scarce and the intimate mechanisms of initiation and development of these highly aggressive and heterogeneous neoplasms remain largely unknown.
Material and Methods: A collection of 18 GCS, including 13 endometrial GCS and 5 ovarian GCS, was established. Two distinct regions of each tumor were dissected and whole genome sequencing, RNA sequencing and methylation array profiling were performed to determine the genomic and DNA methylome landscapes of GCS.
Results: Two GCS were hyper-mutated tumors (mean SNVs = 37,447) with a paucity of structural rearrangements (mean SVs = 18). These two tumors showed a hypermethylation of the MLH1 promoter, one of the two exhibited a frameshift PMS2 mutation and analysis of mutational signatures identified a signature associated with defective DNA mismatch repair (signature 6). All other GCS exhibited a signature associated with failure of DNA double-strand break-repair by homologous recombination (signature 3) and an APOBEC signature (signature 13). Twelve of these tumors were characterized by a high number of structural variants, indicating the onset of genomic instability (mean SV=281; SNV = 9,122), whereas 4 GCS showed a moderate number of structural abnormalities (mean SV=62; SNV = 4,452). The most prominent mutations in GCS were TP53 mutations (94% of tumors), mutations affecting the phosphatidylinositol 3-kinase (PI3K) pathway genes (83%; PTEN, 44%; PIK3CA, 33%; PIK3R1, 17%) and mutations affecting chromatin remodeling genes (78%; including SMARCA4, 28% ; DNMT3B, 22% ; KMT2B, 22%; KMT2C, 22%; NSD2, 17% ; HDAC2, 17%; KMT2E, 11%; ARID1A, 11%). Overall, the co-occurrence of these alterations (TP53 mutations, PI3K alterations and mutations affecting epigenetic modifiers) was found in 72% of tumors (13 out of 18), and 9 tumors showed the three events in the two studied regions. Finally, the evolutionary histories of GCS were evaluated in 5 tumors in which pure carcinomatous and sarcomatous elements were isolated by macrodissection. This analysis demonstrated that these elements shared many somatic mutations, establishing unambiguously the common genetic origin of these malignancies, with sarcomatous elements showing EMT features. The finding that roots mutations in GCS are also frequent in gynecological carcinomas strongly supports an epithelial origin of GCS with a progressive evolution relying upon a transdifferentiation process. This dynamic notion implies that carcinosarcomas are the end result of an evolutionary process and that early forms of GCS may be histologically classified as carcinomas.