Project for Development of Innovative Research on Cancer Therapeutics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan.
Department of Gynecology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan.
Nat Commun. 2019 Oct 31;10(1):4965. doi: 10.1038/s41467-019-12985-x.
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.
子宫或卵巢的癌肉瘤（CS）是一种罕见的、侵袭性的、双相性肿瘤，由癌和肉瘤成分组成。以前的基因组研究已经确定了与 CS 相关的驱动基因和基因组特征。然而，对于这种疾病仍然没有具有临床相关性的分子亚型分类方案。在这里，我们对 109 个 CS 样本进行了测序，重点关注 596 个基因。我们确定了四个与子宫内膜癌相似的分子亚型：POLE 突变型、微卫星不稳定型、拷贝数高型和拷贝数低型。这些分子亚型与 DNA 修复缺陷、潜在的治疗策略以及多个临床病理特征有关，包括患者的预后。多区域比较测序揭示了与基因组改变无关的 CS 细胞分化。转录组和 DNA 甲基组分析证实上皮-间充质转化是肉瘤分化的一种机制。因此，本研究为 CS 提供了治疗的可能性，并为理解其发展的分子发生机制提供了线索。
