LBPO.MCB01 · 分子与细胞生物学 · Late-Breaking
全基因组分析识别日本卵巢癌中新的分子亚型和驱动结构变异
Whole-genome analysis identifies novel molecular subtypes and driver structural variants in Japanese ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌是一种异质性疾病,由多种组织学类型组成,这些类型与不同的临床特征相关,如疗效和复发可能性。由于卵巢癌即使在同一组织学类型内也表现出异质性,因此开发一个互补的分类框架至关重要。对于子宫内膜癌,癌症基因组图谱(TCGA)开发了一个基于基因组特征的分子亚型分类方案,该方案目前已整合到2020年WHO女性生殖道肿瘤分类系统中;而卵巢癌的大规模基因组研究主要集中于高级别浆液性(HGS)——白种人群体中的一种主要组织学类型。其余组织学类型,如在东亚人群中特有高发的透明细胞癌,尚未被这些研究涵盖,因此可用于分子亚型分类的基因组特征在非HGS卵巢癌中尚未得到很好的表征。为填补这一空白,我们对1,412例日本卵巢癌进行了全基因组测序,涵盖六种主要组织学类型:透明细胞癌、高级别浆液性癌、子宫内膜样癌、黏液性癌、癌肉瘤和性索间质肿瘤。整合全基因组分析识别出五种分子亚型——POLE、MSI、CNH-A、CNH-B和CNL——具有不同的基因组和临床病理特征。CNH-A代表一种传统的拷贝数高亚型,以频繁的BRCA1缺失和同源重组缺陷的基因组特征为特征,而CNH-B肿瘤则表现出频繁的ATM改变和保留杂合性的拷贝数变异(CNV)。遗传性癌症基因中的致病性种系变异表现出组织学类型特异性模式,同源重组基因中具有双等位基因改变的肿瘤显示出高HRD评分,并伴有独特的体细胞CNV和结构变异(SV)。此外,在1,349例可评估病例中,我们识别出101个携带候选驱动SV的基因组区域,包括11个已知驱动区域和20个脆性位点,以及70个此前未报道的候选驱动SV区域。总之,这项全基因组分析定义了以独特拷贝数结构为特征的分子亚型,并识别出复发性驱动SV,为精细化的分子分类和未来的精准肿瘤学提供了基础。
查看英文原文 English abstract
Ovarian cancer is a heterogeneous disease comprising a number of histotypes that are associated with distinct clinical characteristics such as therapeutic efficacy and likelihood of relapse. Since ovarian cancer exhibits heterogeneity even within a same histotype, it is critical to develop a complementary classification framework. Whereas for endometrial cancer, a molecular subtyping scheme based on genomic features was developed by The Cancer Genome Atlas (TCGA) and the scheme has been currently integrated into the system of 2020 WHO classification of Female Genital Tract tumour, large-scale genomic studies of ovarian cancer have predominantly focused on high-grade serous (HGS), a major histotype in Caucasian populations. The remaining histotypes exemplified by clear cell carcinoma, which is uniquely prevalent in the East Asian population, have not been covered by these studies, and therefore genomic features that can be utilized for molecular subtyping have not been well characterized for non-HGS ovarian cancer. To address this gap, we performed whole-genome sequencing of 1,412 Japanese ovarian cancers across six major histotypes: clear cell, high-grade serous, endometrioid, mucinous, carcinosarcoma, and sex cord-stromal tumors. Integrative whole-genome analysis identified five molecular subtypes-POLE, MSI, CNH-A, CNH-B, and CNL-with distinct genomic and clinicopathological features. CNH-A represented a conventional copy-number-high subtype characterized by frequent BRCA1 deletions and genomic features of homologous recombination deficiency, whereas CNH-B tumors showed frequent ATM alterations and copy-number variations (CNVs) with retained heterozygosity. Pathogenic germline variants in hereditary cancer genes exhibited histotype-specific patterns, and tumors with biallelic alterations in homologous recombination genes showed high HRD scores, accompanied by distinct somatic CNVs and structural variations (SVs). Furthermore, across 1,349 evaluable cases, we identified 101 genomic regions harboring candidate driver SVs, including 11 known driver regions and 20 fragile sites, as well as 70 previously unreported candidate driver SV regions. Together, this whole-genome analysis defines molecular subtypes characterized by distinct copy-number architectures and identifies recurrent driver SVs, providing a basis for refined molecular classification and future precision oncology.
利益披露 Disclosure
O. Gotoh, None..
T. Ishizuka, None..
N. Tanaka, None..
T. Noda, None..
S. Mori, None.