无特定分子特征的子宫内膜癌的基因组景观。
Genomic landscape of endometrial carcinomas of no specific molecular profile.
机构信息
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
出版信息
Mod Pathol. 2022 Sep;35(9):1269-1278. doi: 10.1038/s41379-022-01066-y. Epub 2022 Apr 1.
Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) as copy number-low (also referred to as "no specific molecular profile" [NSMP]) have a prognosis intermediate between POLE-mutated and copy number-high ECs. NSMP-ECs are a heterogeneous group, however, comprising both relatively indolent and aggressive ECs. We identified a total of 472 NSMP-ECs among 1,239 ECs that underwent clinical sequencing of 410-468 cancer-related genes. Somatic mutation and copy number alteration data were subjected to unsupervised hierarchical clustering, which identified three genomic clusters. Random sampling with stratification was used to choose ~80 endometrioid ECs from each cluster, resulting in a study size of 240 endometrioid ECs as well as an additional 44 non-endometrioid NSMP-ECs. Cluster 1 (C1, n = 80) consisted primarily of NSMP-ECs with PTEN and PIK3R1 mutations, Cluster 2 (C2, n = 81) of tumors with PTEN and PIK3CA mutations and Cluster 3 (C3, n = 79) of NSMP-ECs with chromosome 1q high-level gain and lack of PTEN mutations. The majority (72.7%) of non-endometrioid NSMP-ECs mapped to C3. NSMP-ECs from C3 were more likely to be FIGO grade 3 (30%), estrogen receptor-negative/weak (54.5%) and FIGO stages III or IV. In multivariate analysis, molecular clusters were associated with worse overall survival outcomes with C3 tumors having the worst (hazard ratio: 4) and C1 tumors having the best outcome. In conclusion, NSMP-ECs are a heterogenous group of tumors and comprise both aggressive and clinically low-risk ECs that can be identified based on mutation and copy number data.
子宫内膜癌(EC)根据癌症基因组图谱(TCGA)分类为拷贝数低(也称为“无特定分子谱”[NSMP]),其预后介于 POLE 突变和拷贝数高的 EC 之间。然而,NSMP-EC 是一组异质性群体,包括相对惰性和侵袭性的 EC。我们在对 1239 例接受 410-468 个癌症相关基因临床测序的 EC 中总共鉴定出 472 例 NSMP-EC。对体细胞突变和拷贝数改变数据进行无监督层次聚类,确定了三个基因组簇。通过分层随机抽样,从每个簇中选择约 80 例子宫内膜样 EC,从而得出 240 例子宫内膜样 EC 的研究规模,以及另外 44 例非子宫内膜样 NSMP-EC。簇 1(C1,n=80)主要由具有 PTEN 和 PIK3R1 突变的 NSMP-EC 组成,簇 2(C2,n=81)由具有 PTEN 和 PIK3CA 突变的肿瘤组成,簇 3(C3,n=79)由具有 1q 高水平增益且缺乏 PTEN 突变的 NSMP-EC 组成。大多数(72.7%)非子宫内膜样 NSMP-EC 映射到 C3。C3 中的 NSMP-EC 更有可能是 FIGO 分级 3(30%)、雌激素受体阴性/弱阳性(54.5%)和 FIGO 分期 III 或 IV。多变量分析显示,分子簇与总生存结果相关,C3 肿瘤的预后最差(危险比:4),C1 肿瘤的预后最好。总之,NSMP-EC 是一组异质性肿瘤,包括侵袭性和临床低风险的 EC,可以根据突变和拷贝数数据进行识别。