Zhu Fangfang
The First People's Hospital of Huzhou, No.158, Guangchang Hou Road, Huzhou, 313000, Zhejiang Province, People's Republic of China.
Discov Oncol. 2025 Jul 1;16(1):1218. doi: 10.1007/s12672-025-03039-4.
Breast cancer remains a leading cause of cancer-related mortality worldwide, with intratumoral heterogeneity (ITH) emerging as a critical determinant of treatment outcomes. While ITH's role in therapeutic resistance is increasingly recognized, its interactions with the tumor microenvironment and potential as a prognostic biomarker remain insufficiently explored. This study leverages comprehensive bioinformatic analyses of The Cancer Genome Atlas (TCGA) data to uncover novel ITH-associated prognostic markers in breast cancer. Using the DEPTH2 algorithm for ITH scoring, we demonstrated that high-ITH tumors correlate significantly with poor overall survival. Through differential expression analysis between high- and low-ITH groups, we discovered and validated a novel three-gene signature (CLIC6, SUSD3, and LTF) using Cox regression and stepAIC methodology. External validation using the METABRIC cohort confirmed the signature's robust prognostic significance. Notably, our signature revealed previously unrecognized associations between ITH and the tumor immune microenvironment (TIME), suggesting potential therapeutic implications. Further analysis uncovered significant associations between our ITH-based signature and specific cancer hallmarks, genetic alterations, and clinicopathological features. Our findings not only establish a practical prognostic tool but also provide novel insights into the intricate relationship between tumor heterogeneity and the microenvironment, highlighting potential therapeutic targets for personalized breast cancer treatment.
乳腺癌仍然是全球癌症相关死亡的主要原因，肿瘤内异质性（ITH）已成为治疗结果的关键决定因素。虽然ITH在治疗耐药性中的作用越来越受到认可，但其与肿瘤微环境的相互作用以及作为预后生物标志物的潜力仍未得到充分探索。本研究利用对癌症基因组图谱（TCGA）数据的综合生物信息学分析，以揭示乳腺癌中与ITH相关的新型预后标志物。使用DEPTH2算法进行ITH评分，我们证明高ITH肿瘤与总体生存率差显著相关。通过高ITH组和低ITH组之间的差异表达分析，我们使用Cox回归和stepAIC方法发现并验证了一个新的三基因特征（CLIC6、SUSD3和LTF）。使用METABRIC队列进行的外部验证证实了该特征具有强大的预后意义。值得注意的是，我们的特征揭示了ITH与肿瘤免疫微环境（TIME）之间以前未被认识的关联，提示了潜在的治疗意义。进一步分析发现我们基于ITH的特征与特定癌症特征、基因改变和临床病理特征之间存在显著关联。我们的研究结果不仅建立了一种实用的预后工具，还为肿瘤异质性与微环境之间的复杂关系提供了新的见解，突出了个性化乳腺癌治疗的潜在治疗靶点。
