局部晚期鼻咽癌肿瘤异质性的无创特征：从无进展生存预测到生物学相关性

摘要(中文译文)

局部晚期鼻咽癌(LA-NPC)尽管接受以放疗为基础的治疗，其无进展生存期(PFS)仍表现出显著差异。临床因素和传统影像组学可能无法充分表征瘤内异质性的空间组织特征。拓扑学感知的MRI指标是否与PFS及转录组学特征相关尚不清楚。旨在评估基于MRI的瘤内异质性(ITH)框架用于PFS风险分层，并探讨其在LA-NPC中的转录组学相关性。本研究为回顾性预后建模研究，包含内部验证和独立外部验证，以及一个独立的前瞻性RNA测序队列。回顾性队列纳入1001例患者(男747例，女254例)：训练集n=562；内部验证集n=241；外部验证集n=198。前瞻性RNA测序队列纳入53例患者(男38例，女15例)。治疗前采用3.0-T轴位对比增强T1加权快速/涡轮自旋回波MRI。原发肿瘤由两名资深放射科医师手动分割并审核。采用生存模型评估2D和3D ITH评分及传统影像组学特征。通过差异表达、共表达网络和基因集富集分析评估转录组学相关性。采用一致性指数(C-index)及95%置信区间评估模型区分度。使用Shapley加法解释(SHAP)进行模型解释。转录组学分析采用Benjamini-Hochberg错误发现率(FDR)校正。整合异质性-临床DeepSurv模型在内部验证队列中的C-index为0.727(95% CI，0.674-0.782)，在外部验证队列中为0.714(95% CI，0.661-0.770)。3D ITH评分在模型预测因子中具有最大的平均绝对SHAP值(0.0554)。高3D ITH评分与细胞因子-细胞因子受体相互作用富集(标准化富集评分[NES]=1.57；FDR=0.00705)及病毒蛋白与细胞因子和细胞因子受体信号传导相互作用富集(NES=1.77；FDR=0.00264)相关。基于MRI的3D ITH有助于回顾性PFS风险分层，并显示出探索性的细胞因子相关转录组学相关性，尚需独立验证。3. 第二阶段。

Abstract

Locally advanced nasopharyngeal carcinoma (LA-NPC) shows substantial variability in progression-free survival (PFS) despite radiotherapy-based treatment. Clinical factors and conventional radiomics may not adequately characterize the spatial organization of intratumoral heterogeneity. Whether topology-aware MRI measures are associated with PFS and transcriptomic features remains unclear. To evaluate an MRI-derived intratumoral heterogeneity (ITH) framework for PFS risk stratification and explore its transcriptomic correlates in LA-NPC. Retrospective prognostic modeling study with internal and independent external validation and a separate prospective RNA-sequencing cohort. The retrospective cohort included 1001 patients (747 men and 254 women): training, n = 562; internal validation, n = 241; and external validation, n = 198. The prospective RNA-sequencing cohort included 53 patients (38 men and 15 women). Pretreatment 3.0-T axial contrast-enhanced T1-weighted fast/turbo spin-echo MRI. Primary tumors were manually segmented and reviewed by two senior radiologists. 2D and 3D ITH scores and conventional radiomics features were evaluated using survival models. Transcriptomic correlates were assessed using differential expression, co-expression network, and gene set enrichment analyses. Model discrimination was assessed using the concordance index (C-index) with 95% confidence intervals. Shapley additive explanations (SHAP) were used for model interpretation. Transcriptomic analyses used Benjamini-Hochberg false discovery rate (FDR) correction. The integrated heterogeneity-clinical DeepSurv model yielded C-indices of 0.727 (95% CI, 0.674-0.782) in the internal validation cohort and 0.714 (95% CI, 0.661-0.770) in the external validation cohort. The 3D ITH score had the largest mean absolute SHAP value (0.0554) among the model predictors. High 3D ITH scores were associated with enrichment of cytokine-cytokine receptor interaction (normalized enrichment score [NES] = 1.57; FDR = 0.00705) and viral protein interaction with cytokine and cytokine receptor signaling (NES = 1.77; FDR = 0.00264). MRI-derived 3D ITH contributed to retrospective PFS risk stratification and showed exploratory cytokine-related transcriptomic correlates that require independent validation. 3. Stage 2.

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