Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patients with specific pathological or molecular characteristics and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosomes resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology and may be applicable to the risk stratification of EC. By analyzing CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, the POLE mutant, as a favorable prognostic factor, had elevated CIN signatures, and the CTNNB1 mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE/CTNNB1 mutation stratified stageIendometrioid EC into four groups with improved risk prognostication and treatment recommendations. We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves further improvement and validation.

中文翻译：

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整合病理学、染色体不稳定性和突变对早期子宫内膜样子宫内膜癌的风险分层

子宫内膜癌 (EC) 的风险分层取决于组织病理学和分子病理学。组织病理学风险分层缺乏可重复性，忽略异质性并且对外科手术的贡献很小。现有的分子分层对具有特定病理或分子特征的患者无用，不能指导术后辅助放疗。染色体不稳定性 (CIN) 是由染色体分离的持续错误导致的染色体数量和结构的改变，是组织病理学和分子病理学的不同预后因素演变的内在生物学机制，可能适用于 EC 的风险分层。通过分析 CIN25 和 CIN70 这两个可靠的 CIN 基因表达特征，我们发现具有组织病理学或分子病理学不利预后因素的EC有严重的CIN。然而，作为有利预后因素的 POLE 突变体具有升高的 CIN 特征，而作为不利预后因素的 CTNNB1 突变体具有降低的 CIN 特征。只有排除这两个突变，CIN 特征才能强烈预测不同辅助放疗亚组的结果。将病理学、CIN 特征和 POLE/CTNNB1 突变分层阶段子宫内膜样 EC 分为四组，具有改进的风险预测和治疗建议。我们揭示了通过 CIN 整合组织病理学和分子病理学在早期 EC 中进行风险分层的可能性。我们的综合风险模型值得进一步改进和验证。