Clinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma

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.

Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

“…There have been few previous molecular studies of OCS tumours where the carcinomatous and sarcomatous components have been micro-or macro-dissected 4,5,7 . Two recent studies performed whole exome sequencing on separated components of OCS tumours, but on no more than four tumours each 8,9 . Here, we analysed 377 genes (for mutations, copy number, or both) in 18 OCS tumours where the carcinomatous and sarcomatous components were analysed independently along with associated metastases, where available.…”

“…Molecular analysis suggests that most OCS are monoclonal [4][5][6][7][8][9] , with two theories for OCS histogenesis: the combination theory, where a single stem cell differentiates early to form the two components; and the conversion theory, where the carcinoma undergoes epithelial-tomesenchymal transition (EMT) to form the sarcomatous component 10 .…”

“…TP53 mutations and loss of heterozygosity (LOH) of 17p, and consequent chromosomal instability, are common in OCS 7,8,[11][12][13][14] . Mutations in PIK3CA, PTEN, KRAS, FBXW7, CTNNB1, and RB1 are observed frequently 5,8,9,13,[15][16][17] , whilst mutations in ARID1A, ARID1B, KMT2D, BAZ1A, BRCA1, BRCA2, and RAD51C have also been reported 8,[15][16][17][18][19] . One study also identified recurrent mutations in the genes encoding histones H2A and H2B (HIST1H2AB/C, HIST1H2BB/G/J) that play a role in EMT 9 .…”

“…One study also identified recurrent mutations in the genes encoding histones H2A and H2B (HIST1H2AB/C, HIST1H2BB/G/J) that play a role in EMT 9 . Only one study has analysed gene expression in the separate components, finding a strong positive correlation of EMT score with sarcoma content as well as methylation of the EMT-suppressing miRNAs miR-141/200a/200b/200c/429 8 . EMT can be induced through aberrant expression of the high-mobility-group AT-hook protein 2 (HMGA2) and subsequent activation of the TGF signalling pathway 20 .…”

1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer

“…Most of the "CN high" subtype samples have shared membership with "Mitotic" mRNA subtype and are characterized by highest transcriptional activity in addition to increased dysregulation of the cell cycle pathways (27). Serous subtype cancers of OV and UCEC are considered most aggressive (28). Majority of the serous subtype samples of TCGA UCEC cohort (97 of 109 samples) are also classified as "CN high" tumors and these patients are shown to have poor survival outcomes (27).…”