PO.BCS01.03 · 生物信息与计算
识别并分析p53与拷贝数状态不一致的子宫内膜样子宫内膜肿瘤的临床病理特征
Identifying and analyzing clinicopathological features of uterine endometrial endometrioid tumors discordant by p53 and copy number status
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摘要 Abstract
中文摘要
癌症基因组图谱(TCGA)确定了子宫内膜癌的四种分子亚型:POLE、高微卫星不稳定(MSI-H)、拷贝数低型和拷贝数高型。这些分类最终以ProMisE的形式被采纳进入临床实践,ProMisE是一种基于TCGA的子宫内膜癌分子分类器。TCGA使用层次聚类来定义拷贝数高、低聚类,而ProMisE则利用TP53突变作为拷贝数(CN)高、低亚组的标志物。我们观察到TP53突变判定与拷贝数状态之间存在不一致。我们开发了一种方法,基于肿瘤中是否存在单条染色体臂水平缺失来重新定义CN高型。通过对拷贝数分段数据运行ASCETS算法(靶向测序中的臂水平体细胞拷贝数事件),生成臂水平拷贝数判定。在剔除MMR-D/MSI-H和POLE患者后,我们使用来自TCGA和CPTAC(临床蛋白质组肿瘤分析联盟)数据的分子亚型验证了该方法,准确率分别为0.823和0.865。接下来,我们将该方法应用于446例使用新一代靶向测序面板(OncoPanel)进行分析的子宫内膜样子宫内膜肿瘤队列。剔除MSI-H/POLE肿瘤后,我们发现167例肿瘤在CN与TP53突变状态上一致(31例CN高型/TP53突变型;136例CN低型/TP53野生型),92例不一致(84例CN高型/TP53野生型;8例CN低型/TP53突变型)。按TP53突变和由臂水平缺失判定的拷贝数状态分层的生存分析显示,同时具有TP53突变和高拷贝数的患者在CPTAC(p = 0.027)和OncoPanel(p < 0.0001)两个队列中总生存期均显著较差,但TP53野生型/CN高型与TP53野生型/CN低型患者之间的生存无显著差异。总体而言,我们发现TP53野生型肿瘤无论拷贝数状态如何,预后相似,并且还发现CN高型/TP53突变型肿瘤的预后可能显著差于CN低型/TP53突变型肿瘤(p = 0.036)。将使用更多数据来证实这一点。
查看英文原文 English abstract
The Cancer Genome Atlas (TCGA) identified four molecular subtypes of endometrial carcinoma: POLE, high microsatellite instability (MSI-H), copy number-low and copy number-high. These classifications were eventually adopted into clinical practice in the form of ProMisE, a molecular classifier for endometrial cancers based on TCGA. While TCGA used hierarchical clustering to define copy-number high and low clusters, ProMisE utilizes TP53 mutation as a marker of the copy-number (CN) high and low subgroups. We have observed discordances between TP53 mutation call and copy-number status. We developed a method to redefine CN-high based on the presence of a single chromosomal arm-level deletion in a tumor. Arm-level copy number calls were generated by running the algorithm ASCETS (Arm-level Somatic Copy-number Events in Targeted Sequencing) on copy number segmentation data to give arm-level copy number calls. We validated this approach using molecular subtypes from both TCGA and CPTAC ( Clinical Proteomic Tumor Analysis Consortium ) data after taking out MMR-D/MSI-H and POLE patients, yielding accuracies of 0.823 and 0.865, respectively. Next, we applied this approach to a cohort of 446 endometrioid endometrial tumors profiled using a next-generation targeted sequencing panel (OncoPanel). After removing MSI-H/POLE tumors, we found 167 tumors concordant with regards to CN and TP53 mutation status (31 CN-high/ TP53 mutant; 136 CN-low/ TP53 wild-type), and 92 discordant tumors (84 CN-high/ TP53 wild-type; 8 CN-low/ TP53 mutant). Survival analysis stratified by TP53 mutation and copy number status called by arm-level deletion yields significantly worse overall survival for patients with both TP53 mutation and high copy number in both the CPTAC (p = 0.027) and OncoPanel (p < 0.0001) cohorts, but no significant difference in survival between TP53 WT/CN-high and TP53 WT/CN-low patients. Overall, we find that TP53 WT tumors have similar prognosis regardless of copy number status and have also found that CN-high/ TP53 mutant tumors may have significantly worse prognosis than CN-low/ TP53 mutant tumors (p = 0.036). Additional data will be used to confirm this.
利益披露 Disclosure
S. B. Challa, None..
J. D. St. Laurent, None..
Z. Ordulu, None..
A. J. Neil, None..
M. S. Gildenberg, None.
M. L. Meyerson,
Bayer ), Patent, Other.
Janssen ).
Delve Bio Other.
Isabl Other.
Karyoverse Other.
Y. Y. Li, None.
A. D. Cherniack,
Bayer Other.
E. H. Stover, None.