Abstract
Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. Previous genomic studies have identified the driver genes and genomic properties associated with CS. However, there is still no molecular subtyping scheme with clinical relevance for this disease. Here, we sequence 109 CS samples, focusing on 596 genes. We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Multi-regional comparative sequencing reveals genomic alteration-independent CS cell differentiation. Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development.
Highlights
Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements
We used a modified version of the molecular subtyping method based on genomic aberration profiling[16] on 109 uterine and ovarian CS samples, and used a decision tree to classify samples into four molecular subtypes: polymerase ε (POLE)-mutated (POLE), microsatellite instability (MSI), copy number high (CNH), and copy number low (CNL) subtypes
POLE is designated by a somatic POLE mutation in the exonuclease domain, and is characterized by a substantial number of SNVs with a variable number of indels and copy number variants (CNV)
Summary
Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Even though several clinicopathological assessments have identified multiple independent prognostic factors for CS7,15, the molecular basis of the aggressiveness of this disease is still largely unknown. There is a clinical demand to discover actionable molecular targets as well as biomarkers for prognostication and patient stratification
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