PO.MCB08.05 · 分子与细胞生物学
卵巢癌肉瘤与子宫癌肉瘤之间的分子差异
Molecular differences between ovarian and uterine carcinosarcomas
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌肉瘤，又称恶性苗勒管混合瘤（MMMT），是一类罕见且侵袭性强的肿瘤，其特征为同时存在癌性（上皮）成分和肉瘤性（间叶）成分。这些肿瘤主要发生于子宫，较少见于卵巢。尽管组织学上相似，卵巢癌肉瘤与子宫癌肉瘤在流行病学、临床表现、预后和治疗策略上存在差异。理解卵巢癌肉瘤与子宫癌肉瘤之间的分子差异，对于准确诊断、有效治疗规划和改善患者预后至关重要。在本研究中，我们对三例卵巢癌肉瘤和三例子宫癌肉瘤及其配对的正常血液或组织DNA进行了全外显子组测序（WES）。测序文库使用Twist Library Preparation and Capture Kit制备，并在NovaSeq X 25B上以150 bp双端读长测序，每个样本平均生成超过9亿个读段。在各样本中鉴定出体细胞变异（错义突变和indel；n=1,971-2,542）。值得注意的是，在六例癌肉瘤中的五例检出TBC1D32（p.Thr375Lys）的新型胚系突变。TBC1D32主要与纤毛病和垂体功能减退等遗传疾病相关，尽管在多种癌症中曾报道过其突变，但其作为癌基因或抑癌基因的作用仍不明确。虽然卵巢癌肉瘤与子宫癌肉瘤之间的变异总数无显著差异，但若干体细胞变异为卵巢癌肉瘤所独有，包括ANKDD1A和RPL10的改变。ANKDD1A具有抑癌功能，在胶质母细胞瘤中常通过高甲基化而沉默。RPL10通过蛋白质合成和核糖体外功能影响癌症，其过表达和突变与肿瘤发生相关。这些变异在更多癌肉瘤样本中的验证正在进行中。此外，我们正在使用Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus Kit和NovaSeq X 25B（100 bp双端读长）进行RNA测序，以识别卵巢癌肉瘤与子宫癌肉瘤之间的差异表达基因。数据分析目前正在进行中。总之，我们在卵巢癌肉瘤和子宫癌肉瘤中均鉴定出TBC1D32（p.Thr375Lys）的复发性胚系突变，以及卵巢癌肉瘤所独有的体细胞变异。对这些基因的进一步研究可能有助于揭示癌肉瘤的发病机制，并为卵巢与子宫疾病的差异化治疗策略的开发提供依据。
查看英文原文 English abstract
Carcinosarcomas, also known as malignant mixed Müllerian tumors (MMMTs), are rare and aggressive neoplasms characterized by the coexistence of both carcinomatous (epithelial) and sarcomatous (mesenchymal) components. These tumors primarily arise in the uterus and less frequently in the ovary. Despite histological similarities, ovarian and uterine carcinosarcomas differ in epidemiology, clinical presentation, prognosis, and treatment strategies. Understanding the molecular differences between ovarian and uterine carcinosarcoma is essential for accurate diagnosis, effective treatment planning, and improved patient outcomes.In this study, whole-exome sequencing (WES) was performed on three ovarian and three uterine carcinosarcomas, along with matched normal blood or tissue DNA. Sequencing libraries were prepared using the Twist Library Preparation and Capture Kit and sequenced on NovaSeq X 25B with 150 bp paired end reads, generating an average of >900 million reads per sample.Somatic variants (missense and indels; n = 1,971-2,542) were identified across samples. Notably, a novel germline mutation in TBC1D32 (p.Thr375Lys) was detected in five of the six carcinosarcomas. TBC1D32 is primarily associated with genetic disorders such as ciliopathies and hypopituitarism, and although mutations have been reported in various cancers, its role as an oncogene or tumor suppressor remains unclear. While the overall number of variants did not differ significantly between ovarian and uterine carcinosarcomas, several somatic variants were unique to ovarian carcinosarcoma, including alterations in ANKDD1A and RPL10. ANKDD1A functions as a tumor suppressor; frequently silenced in glioblastoma via hypermethylation. RPL10 influences cancer through protein synthesis and extra-ribosomal functions; overexpression and mutations linked to tumor development. Validation of these variants in additional carcinosarcoma samples is ongoing. Furthermore, RNA sequencing using the Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus Kit and NovaSeq X 25B (100 bp paired-end reads) is being conducted to identify differentially expressed genes between ovarian and uterine carcinosarcomas. Data analysis is currently in progress. In conclusion, we identified a recurrent germline mutation in TBC1D32 (p.Thr375Lys) across both ovarian and uterine carcinosarcomas, as well as somatic variants unique to ovarian carcinosarcoma. Further investigation of these genes may provide insights into carcinosarcoma pathogenesis and inform the development of differential treatment strategies for ovarian versus uterine disease.
利益披露 Disclosure
K. Wong, None..
Y. Tsang, None.