Uterine cancer is the 6th leading cause of cancer death amongst American women. Most uterine cancers are endometrial carcinomas (ECs), which are classified into histological subtypes including endometrioid, serous, and clear cell ECs. Somatic copy number alterations (SCNAs) are frequent in serous EC, infrequent in endometrioid ECs, and poorly defined in clear cell ECs. The purpose of this study was to evaluate the occurrence of SCNAs in clinically diagnosed clear cell ECs. Paired tumor-normal DNAs for 51 ECs were hybridized to Illumina Infinium HumanHap650Y or Human660W-Quad Beadchips. Copy number calls were made using the Hidden Markov Model based SNP-FASST2 segmentation algorithm within Nexus Copy Number software (v.6.1). High-level SCNAs were defined as gain of ≥5 copies or homozygous deletion, both <10Mb. GISTIC 1.0, in Nexus, was used to identify statistically significant SCNAs, corrected for multiple testing. One or more high-level SCNAs were detected in 50% of 6 clear cell ECs, 78.6% of 28 serous ECs, and 17.6% of 17 endometrioid ECs. A positive association was found between high-level SCNAs and TP53 mutation across ECs (two-tailed p value<0.0001). Classifying tumors according to POLE, MSI, and TP53 status yielded four molecular subgroups; copy number altered tumors were more frequent in the TP53-mutated subgroup (95.8%) than in the unspecified subgroup (22.2%), and absent from the POLE and MSI subgroups. In conclusion, our study provides evidence of inter-tumor heterogeneity in the extent to which SCNAs occur in clinically diagnosed clear cell EC, and across molecular subgroups of EC. The co-occurrence of high-level SCNAs and TP53 mutations in some clear cell ECs is consistent with the view that a subset of clinically diagnosed clear cell ECs have molecular similarities to serous ECs.

子宫癌是美国女性中第六大癌症死因。大多数子宫癌是子宫内膜癌（EC），可分为组织学亚型，包括子宫内膜样，浆液性和透明细胞EC。体细胞拷贝数改变（SCNA）在浆液性EC中很常见，在子宫内膜样EC中不常见，而在透明细胞EC中定义较差。这项研究的目的是评估临床诊断的透明细胞EC中SCNA的发生。将51个EC的配对肿瘤正常DNA与Illumina Infinium HumanHap650Y或Human660W-Quad Beadchips杂交。使用Nexus Copy Number软件（v.6.1）中基于Hidden Markov Model的SNP-FASST2分段算法进行了副本编号呼叫。高级SCNA定义为≥5个拷贝或纯合缺失，均<10Mb。Nexus中的GISTIC 1.0，用于识别具有统计意义的SCNA，并针对多次测试进行了更正。在6个透明细胞EC的50％，28个浆液性EC的78.6％和17个子宫内膜样EC的17.6％中检测到一种或多种高水平SCNA。发现高级别SCNA与跨EC的TP53突变（两尾p值<0.0001）。根据POLE，MSI和TP53状态对肿瘤进行分类产生了四个分子亚组。TP53突变的亚组（95.8％）比未指定的亚组（22.2％）更频繁地出现拷贝数改变的肿瘤，而POLE和MSI亚组则没有。总之，我们的研究提供了在临床诊断的透明细胞EC以及整个EC分子亚组中SCNA发生程度的肿瘤间异质性证据。高级别SCNA与TP53并存 一些透明细胞EC中的突变符合以下观点：临床诊断的透明细胞EC的子集与浆液EC具有分子相似性。