將VHL定義為乳癌的預後生物標記及其表觀遺傳特徵分析

Defining VHL as a Prognostic Biomarker and its Epigenetic Profiling for Breast Cancer

雖然希佩爾-林道氏病腫瘤抑制因子(VHL)突變的功能已被廣泛研究，但其在乳癌中的全面分析尚未完全闡明。本研究旨在定義VHL基因變異與腫瘤突變負荷和微生物組譜的關係，其在乳癌患者診斷和預後中的重要性，以及探索其表觀遺傳景觀。訪問TCGA樣本以分析VHL基因變異與TMB和微生物組譜的關係。從TCGA檢索的臨床記錄和轉錄組學數據用於調查診斷和預後的重要性。GEO被用作驗證數據集。蛋白質組學數據來自CPTAC。表觀基因組學數據用於檢查啟動子甲基化水平。通過ROC Plotter評估VHL表達對化療蒽環類藥物的預測準確性。通過檢索Dependency Map（DepMap）門戶資源的基因敲除數據評估VHL對乳癌細胞的生存影響。VHL擴增和高mRNA與低甲基化相關，而VHL變異與突變數量、TMB和微生物組特徵無關。腫瘤表現出比正常組織更高的VHL基因和蛋白質表達水平。低VHL基因表達預測臨床對蒽環類藥物的反應者。VHL與MKI67表達的正相關表明其預後價值。高VHL表達與較短的總生存期和疾病特異性生存期相關。VHL的缺失導致23種乳癌細胞系的生存能力降低。注意到腫瘤中VHL啟動子的低甲基化和高乙酰化。總體而言，本研究揭示了VHL表達水平在診斷、預後、化療反應預測和癌症生存中的影響，並揭示了其表觀遺傳變化。

While the function of Von Hippel-Lindau tumor suppressor (VHL) mutations has been extensively studied, its comprehensive analysis in breast cancer is yet to be fully elucidated. This study aims to define the relationship of VHL genetic alterations with the landscape of the tumor mutation burden (TMB) and the microbiome profile, its significance in diagnosis and prognosis for breast cancer patients, as well as to explore its epigenetic landscape. TCGA samples were accessed to analyze the relationship of VHL genetic alterations with the landscape of TMB and the microbiome profile. Clinical records and transcriptomics data retrieved from TCGA were used to investigate significance in diagnosis and prognosis. Gene Expression Omnibus (GEO) datasets were utilized for validation. Proteomics data were accessed from CPTAC. Epigenomics data were used to examine promoter methylation levels. The predictive accuracy of VHL expression on anthracycline-based chemotherapy was evaluated using ROC Plotter. The impact of VHL on breast cancer cell viability was assessed by retrieving gene knockout data from the Dependency Map (DepMap) portal resource. VHL amplification and high mRNA expression were associated with hypomethylation, while VHL alterations showed no correlation with mutation counts, TMB, or microbiome signatures. Tumors exhibited higher gene and protein expression levels of VHL compared to normal tissues. Low VHL gene expression predicted clinical response to anthracycline. The positive correlation of VHL with MKI67 expression indicates its prognostic value. High VHL expression was associated with shorter overall survival (OS) and disease-specific survival (DSS). Loss of VHL led to reduced viability in 23 breast cancer cell lines. Hypomethylation and hyperacetylation of the VHL promoter in tumors were noted. Collectively, this study reveals the implications of VHL expression levels in diagnosis, prognosis, prediction of chemotherapeutic response, and cancer survival, as well as sheds light on its epigenetic alterations.