Journal Article

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

Sugiyama, Yuko, Takeshima, Nobuhiro, Mori, Seiichi, Kato, Kazuyoshi, Taki, Mana, Omatsu, Kohei, Fujiwara, Keiichi, Tanaka, Norio, Nomura, Hidetaka, Gotoh, Osamu, Takazawa, Yutaka, Matsumura, Noriomi, Noda, Tetsuo, Hasegawa, Kosei

2019

Overview

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. Carcinosarcoma of the ovary or uterus comprises both carcinoma and sarcoma elements. Here, the authors perform a multi -omics study of the disease revealing therapeutic possibilities for this rare and aggressive disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/91 / 631/67/1517 / 631/67/69 / Adult / Aged / Aged, 80 and over / Cancer / Carcinoma / Carcinoma, Endometrioid - genetics / Carcinoma, Endometrioid - pathology / Carcinosarcoma - classification / Carcinosarcoma - genetics / Carcinosarcoma - pathology / Cell differentiation / Clinical outcomes / Cluster Analysis / Copy number / Decision Trees / Deoxyribonucleic acid / Differentiation (biology) / Disease / DNA / DNA Copy Number Variations - genetics / DNA Methylation / DNA Polymerase II - genetics / DNA repair / DNA Repair-Deficiency Disorders - genetics / DNA sequencing / Endometrial cancer / Endometrium / Epithelial-Mesenchymal Transition - genetics / Female / Gene expression / Genes / Genital Neoplasms, Female - genetics / Genomes / Genomics / Genotype & phenotype / High-Throughput Nucleotide Sequencing / Histology / Hospitals / Humanities and Social Sciences / Humans / INDEL Mutation / Medical prognosis / Medical research / Menopause / Mesenchyme / Microsatellite Instability / Middle Aged / multidisciplinary / Mutation / Neoplasms, Cystic, Mucinous, and Serous - genetics / Neoplasms, Cystic, Mucinous, and Serous - pathology / Ovarian Neoplasms - classification / Ovarian Neoplasms - genetics / Ovarian Neoplasms - pathology / Ovaries / Peritoneal Neoplasms - genetics / Poly-ADP-Ribose Binding Proteins - genetics / Polymorphism, Single Nucleotide / RNA, Messenger - metabolism / Sarcoma / Science / Science (multidisciplinary) / Sequence Analysis, DNA / Transcriptome / Tumors / Uterine cancer / Uterine Neoplasms - classification / Uterine Neoplasms - genetics / Uterine Neoplasms - pathology / Uterus / Young Adult