晝夜節律基因在乳癌診斷、預後和治療反應的綜合分析

Comprehensive Analysis of Circadian Genes in Diagnosis, Prognosis and Treatment Response in Breast Cancer

乳癌是全球女性患者癌症相關死亡率的主要原因。晝夜節律基因與人類癌症之間的相關性已被確立，但對晝夜節律基因的臨床意義的綜合分析卻很少。分別使用TNMplot和KM Plotter網站工具確定基因表現的診斷和預後意義的分析。採用TNMplot的相關分析模組來分析從癌症基因組圖譜（TCGA）檢索的乳癌患者資料中兩個基因的Spearman相關性。使用基於公開存取的基因晶片資料庫的數據ROC曲線分析，以評估藥物反應的預測能力。KLF9、THRAP3、NPAS2、KLF9、CSNK1E和CSNK1D等晝夜節律基因中，在包括BRCA在內的大多數癌症類型中，KLF9在腫瘤中的表現量顯著低於正常組織。KLF9低表現與BRCA患者總存活時間較短有關。KLF9與已知的預後生物標記MKI67、PCNA、MCM2和GMNN呈現顯著負相關。在淋巴結陽性的BRCA患者中，抗HER2治療有反應者中觀察到KLF9低表現。值得注意的是，低/高KLF9表達量在抗HER2治療反應中表現出良好的預測準確性，曲曲線下面積達0.708。總之，KLF9的低表現可以作為乳癌以及多種癌症類型的差異生物標記。KLF9的低表現顯示病患預後較差，且預測淋巴結陽性的患者對抗HER2治療有良好的治療反應，為開發新的預後組和治療方法提供了可能的途徑。

Breast cancer (BRCA) accounts for cancer-related mortality in female patients across the world. A correlation between circadian rhythm genes and human cancers has been established, while a comprehensive analysis of the clinical significance of circadian rhythm genes is scarce. Analysis of diagnostic and prognostic significance of gene expression was determined using the TNMplot web portal and KM Plotter, respectively. The correlation analysis module of TNM plot was employed to analyze the Spearman correlation of two genes in BRCA patients’data retrieved from The Cancer Genome Atlas (TCGA). Publicly accessed gene-chip databases were used to perform Receiver Operating Characteristic (ROC) analysis for assessment of predictive ability for drug response. Among circadian rhythm genes such as KLF9, THRAP3, NPAS2, KLF9, CSNK1E and CSNK1D, KLF9 showed remarkably lower expression levels in tumors than normal tissue in the majority of cancer types, including BRCA. Low expression of KLF9 was associated with shorter overall survival time of patients with BRCA. KLF9 showed a significant negative correlation with well-known prognostic biomarkers MKI67, PCNA, MCM2 and GMNN. In BRCA patients with nodal positivity, low expression of KLF9 was noticed in responders to anti-HER2 therapy. Notably, low/high KLF9 expression levels presented good predictive accuracy in anti-HER2 therapy response, with an AUC of 0.708. In conclusion, low expression of KLF9 can serve as a differential biomarker for BRCA tumors as well as several cancer types. Low expression of KLF9 indicates poor outcomes and predicts favorable treatment responses of those with nodal positivity to anti-HER2 therapy, rendering a possible path to the development of new prognostication panels and therapeutic approaches.