Molecular classification and subtype-specific drug sensitivity research of uterine carcinosarcoma under multi-omics framework

Abstract

Objective: Uterine carcinosarcomas (UCSs) are aggressive rare tumors recognized as malignancies composed of metaplastic transformation of epithelial elements. Nay no comprehensive molecular classification has been applied to UCS to guide targeted therapies so far, which motivated us to subtyping UCS by aggregating multiple genomic platform data. Methods: We classified UCS into three distinct subtypes with different clinicopathologic and molecular characterization by using similarity network fusion under consensus clustering framework (SNFCC +) to aggregate four genomic data platforms of 55 UCS patients. Differences across subtypes were extracted by functional enrichment, gene mutations and clinical features. Subtypes were further distinguished by putative biomarkers. We also determined associations between individual oncogenes and chemotherapeutics to discuss subtype-specific drug sensitivity. Results: Functional enrichment analysis of the subtype-specific differential expression genes endowed three subtypes new designation: Myo, Cell and Hormone. Mutations in PTEN, PIK3CA, ARID1A and PPP2R1A altered across subtypes. The epithelial-to-mesenchymal transition (EMT) score distinguished Myo from another two subtypes whereby a high EMT scores prevalently existed and each case was judged as M (mesenchymal) phenotype in Myo subtype. Through the drug sensitivity analysis, we found that the response totinib drugs is quite different across subtypes according to expression level. Additionally, different subtypes' response to broad-spectrum anti-cancer drug paclitaxel may be also different. Conclusions: In this study, we identified three distinct molecular subtypes of UCS with different features. Subtypes were also revealed to have different sensitivity to existing chemotherapy drugs, which may support in-depth study of subtype-specific dosing regimens.

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma

“…Moreover, overexpression of genes encoding specialized cytoskeletal proteins, such as slow ( Myh7 ) and embryonic ( Myh3 ) myosin heavy chains and skeletal α-actin ( Acta1 ), was also observed. Similar to our previous results, Lu et al [94] reported that 18 out of 57 ECS reported in the TCGA had a gene expression pattern enriched in genes involved in muscle development and morphogenesis, myoblast differentiation, and contraction regulation.…”

Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma

“…Although confined to the corpus, the recurrence rate of UCS still remains very high, the development and recurrence of which might aggravate the tumor and lead to a poor prognosis [ 6 ]. Several studies explored potential prognosis-related genes of UCS [ 6 , 7 ], and a novel study classified UCS into different subtypes with distinct molecular and clinicopathologic features to improve subtype-specific therapeutic regimens [ 8 ]. Nevertheless, the complicated heterogeneity and low frequency of UCS indicate that related researches are insufficient and further study on the pathogenesis of UCS and exploration of novel biomarkers for the improvement of the prognostic prediction of patients with UCS are urgently required.…”