PO.CL09.01 · 临床研究

妇科肿瘤生存的基因组和祖源相关决定因素

Genomic and ancestry-associated determinants of survival in gynecologic cancers

编号 5352 展板 20 时间 4/21 09:00–12:00 区域 Section 46 主讲 Laura Chambers, MS

分会场 Precision Oncology and Real World Data

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Laura Chambers¹, Avinash Ramu², Vasily N. Aushev², Susan Rojahn², Alyssa Antonopoulos², Carly B. Scalise², Faraz Salmasi², Minetta C. Liu², Adam C. ElNaggar², Rebecca C. Arend³

¹The Ohio State University, Columbus, OH,²Natera, Inc., Austin, TX,³Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL

摘要 Abstract

中文摘要

妇科肿瘤的生存结局在不同人群间存在差异；然而，导致这些差异的基因组和其他因素尚未明确界定。我们利用一个大型真实世界数据集，考察遗传祖源、肿瘤基因组学和组织学如何与子宫内膜癌（EC）、卵巢癌（OC）和宫颈癌（CC）的总生存期（OS）相关。这项回顾性分析使用了Natera专有的去标识化真实世界数据库中整合的全外显子组测序（WES）、医疗理赔、死亡记录和电子健康记录数据。肿瘤和胚系WES数据是作为一项个体化、肿瘤指导的mPCR-NGS循环肿瘤DNA检测（Signatera™，Natera Inc.）工作流程的一部分获得的。分析了变异、微卫星不稳定性（MSI）和遗传祖源。祖源通过EthSeq推断，并分类为预定义组别：非洲（AFR）、美洲、东亚（EAS）、欧洲（EUR）和南亚。使用自然语言处理从临床记录中提取癌症组织学类型。使用Cox比例风险模型评估OS关联。共纳入2,574例EC、2,425例OC和773例CC患者。在EC中，AFR祖源与较差的OS相关（相比EUR祖源，HR 1.56，p=0.013），尤其是在I/II期患者中（HR 2.1，p=0.03）。EC中最常见的变异发生在PTEN（46.5%的患者）、PIK3CA（40.6%）、TP53（38.0%）和ARID1A（37.8%）。TP53变异（I/II期：HR 2.1，p<0.001；III/IV期：HR 2.1，p<0.0001）和KMT2B变异（III/IV期：HR 1.48，p=0.04）与较差的OS相关，而PTEN变异（I/II期：HR 0.5，p=0.002；III/IV期：HR 0.44，p<0.0001）和ARID1A变异（I/II期：HR 0.6，p=0.02；III/IV期：HR 0.5，p<0.0001）与较好的OS相关。微卫星稳定（MSS）EC肿瘤的OS较MSI高者更差（MSS vs MSI-H：HR 2.0，p<0.001）。在OC中，I期AFR患者的OS较EUR患者更差（HR 7.5，p=0.04）。OC肿瘤变异最常见于TP53（59.7%）、PIK3CA（11.4%）和ARID1A（10.5%），与已确立的OC生物学一致。未发现OS与变异、MSI或组织学的关联。在CC中，AFR祖源与较差的OS相关（相比EUR，HR 2.0，p=0.04）。PIK3CA变异常见（29.5%的患者），并在II/III/IV期患者中与较差的OS相关（HR 1.9，p=0.015）。未观察到按组织学的OS差异。在各类癌症中，AFR和EAS祖源相比EUR呈现出不同的组织学分布。总之，遗传祖源在各妇科肿瘤中与OS独立相关，尤其是在AFR祖源的EC和CC患者中。特定的基因组特征（如MSI状态和TP53、PTEN、ARID1A、PIK3CA及KMT2B变异）进一步界定了风险。将祖源信息化的基因组和病理数据进一步纳入临床研究可能减少妇科恶性肿瘤的生存差异。

查看英文原文 English abstract

Survival outcomes for gynecologic cancers vary across populations; however, the genomic and other factors that contribute to these differences are poorly defined. We leveraged a large, real-world dataset to examine how genetic ancestry, tumor genomics, and histology are associated with overall survival (OS) in endometrial (EC), ovarian (OC), and cervical cancer (CC). This retrospective analysis used integrated data from whole-exome sequencing (WES), medical claims, mortality records, and electronic health records in Natera's proprietary de-identified Real-World Database. Tumor and germline WES data were obtained as part of the workflow for a personalized, tumor-informed mPCR-NGS circulating-tumor DNA assay (Signatera TM , Natera Inc.). Variants, microsatellite instability (MSI), and genetic ancestry were analyzed. Ancestry was inferred by EthSeq and classified into predefined groups: African (AFR), American, East Asian (EAS), European (EUR), and South Asian. Cancer histologies were extracted from clinical records using natural language processing. OS associations were evaluated using Cox proportional hazards models. A total of 2,574 EC, 2,425 OC, and 773 CC patients were included. In EC, AFR ancestry was associated with worse OS compared to EUR ancestry (HR 1.56, p=0.013), especially in stage I/II patients (HR 2.1, p=0.03). The most frequent variants in EC were in PTEN (46.5% of patients), PIK3CA (40.6%), TP53 (38.0%), and ARID1A (37.8%). Variants in TP53 (stage I/II: HR 2.1, p<0.001; stage III/IV: HR 2.1, p<0.0001) and KMT2B (stage III/IV: HR 1.48, p=0.04) were linked with worse OS, while variants in PTEN (stage I/II: HR 0.5, p=0.002; stage III/IV: HR 0.44, p<0.0001) and ARID1A (stage I/II: HR 0.6, p=0.02; stage III/IV: HR 0.5, p<0.0001) were associated with better OS. Microsatellite stable (MSS) EC tumors had a worse OS than MSI-High (MSS vs MSI-H: HR 2.0, p<0.001). In OC, stage I AFR patients had worse OS compared to EUR patients (HR 7.5, p=0.04). OC tumor variants were most common in TP53 (59.7%), PIK3CA (11.4%) , and ARID1A (10.5%), consistent with established OC biology. No associations with OS and variants, MSI, or histology were identified. In CC, AFR ancestry was associated with worse OS vs EUR (HR 2.0, p=0.04). PIK3CA variants were common (29.5% of patients) and associated with worse OS in stage II/III/IV patients (HR 1.9, p=0.015). No OS differences by histology were observed. Across cancers, AFR and EAS ancestry showed distinct histologic distributions compared with EUR. In conclusion, genetic ancestry was independently associated with OS across gynecologic cancers, particularly among AFR-ancestry patients with EC and CC. Specific genomic features (e.g., MSI status and TP53 , PTEN , ARID1A, PIK3CA, and KMT2B variants) further define risk. Further study of ancestry-informed genomic and pathologic data into clinical research may reduce survival disparities in gynecologic malignancies.

利益披露 Disclosure

L. Chambers, None. A. Ramu, Natera, Inc. Employment, Stock, Stock Option. V. N. Aushev, Natera, Inc. Employment, Stock, Stock Option. S. Rojahn, Natera, Inc. Employment, Stock Option. A. Antonopoulos, Natera, Inc. Employment, Stock, Stock Option. C. B. Scalise, Natera, Inc. Employment, Stock, Stock Option. F. Salmasi, Natera, Inc. Employment, Stock, Stock Option. M. C. Liu, Natera, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option. A. C. ElNaggar, Natera, Inc. Employment, Stock, Stock Option. R. C. Arend, None.

← 返回 AACR 2026 检索