【佳學基因檢測】基于 NMR 的代謝組學分析確定了 RON-DEK-β-連環(huán)蛋白依賴性代謝途徑和對乳腺癌患者生存進行分層的基因特征

基因突變怎么治療秘決

課題調(diào)研《腫瘤突變基因檢測與個性化治療方案的制定》《PLoS One》在.?2022 Sep 6;17(9):e0274128.發(fā)表了一篇題目為《基于 NMR 的代謝組學分析確定了 RON-DEK-β-連環(huán)蛋白依賴性代謝途徑和對乳腺癌患者生存進行分層的基因特征》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Sara Vicente-Mu?oz,?Brian G Hunt,?Taylor E Lange,?Susanne I Wells,?Susan E Waltz等完成。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調(diào)了基因信息檢測與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究內(nèi)容關(guān)鍵詞：

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

背景：檢測技術(shù)和治療的進步提高了早期乳腺癌的診斷率；然而，所有乳腺癌亞型都會發(fā)生反復，并且反復性和新發(fā)轉(zhuǎn)移通常都具有治療抗性。越來越多的證據(jù)支持代謝可塑性驅(qū)動癌癥反復的觀點。 RON 和 DEK 是促進癌癥轉(zhuǎn)移并在機械上協(xié)同激活 β-連環(huán)蛋白的蛋白質(zhì)，但代謝后果尚不清楚。方法：為了確定 RON-DEK-β-連環(huán)蛋白依賴性代謝途徑，我們利用基于 NMR 的代謝組學方法來確定代謝物的穩(wěn)態(tài)水平。我們還研究了改變的代謝途徑基因表達對乳腺癌患者無反復和無遠處轉(zhuǎn)移生存的預(yù)后能力的影響，并發(fā)現(xiàn)了可能與反復相關(guān)的代謝特征。結(jié)果：RON-DEK-β-連環(huán)蛋白丟失顯示出一致的代謝物調(diào)節(jié)琥珀酸和磷酸肌酸。在培養(yǎng)基葡萄糖消耗、乳酸分泌、乙酸分泌以及細胞內(nèi)谷氨酰胺和谷胱甘肽水平中發(fā)現(xiàn)了 RON 和 DEK 損失（但不是 β-連環(huán)蛋白）之間一致的代謝物改變。僅在細胞內(nèi)乳酸水平中發(fā)現(xiàn) RON 和 β-連環(huán)蛋白丟失（而不是 DEK）之間一致的代謝物改變。其他途徑命中包括 β-連環(huán)蛋白，包括糖酵解、糖基化、TCA 循環(huán)/回補、NAD+ 產(chǎn)生和肌酸動力學。這些通路中對 RON-DEK-β-catenin 上位性的基因被用來定義預(yù)測乳腺癌患者生存和對化療反應(yīng)的基因特征。結(jié)論：RON-DEK-β-catenin 軸調(diào)節(jié)具有顯著關(guān)聯(lián)的眾多代謝途徑對乳腺癌患者的結(jié)果。

腫瘤發(fā)生與反復轉(zhuǎn)移國際數(shù)據(jù)庫描述：

Background:?Advances in detection techniques and treatment have increased the diagnosis of breast cancer at early stages; however, recurrence occurs in all breast cancer subtypes, and both recurrent and de novo metastasis are typically treatment resistant. A growing body of evidence supports the notion that metabolic plasticity drives cancer recurrence. RON and DEK are proteins that promote cancer metastasis and synergize mechanistically to activate β-catenin, but the metabolic consequences are unknown.Methods:?To ascertain RON-DEK-β-catenin dependent metabolic pathways, we utilized an NMR-based metabolomics approach to determine steady state levels of metabolites. We also interrogated altered metabolic pathway gene expression for prognostic capacity in breast cancer patient relapse-free and distant metastasis-free survival and discover a metabolic signature that is likely associated with recurrence.Results:?RON-DEK-β-catenin loss showed a consistent metabolite regulation of succinate and phosphocreatine. Consistent metabolite alterations between RON and DEK loss (but not β-catenin) were found in media glucose consumption, lactate secretion, acetate secretion, and intracellular glutamine and glutathione levels. Consistent metabolite alterations between RON and β-catenin loss (and not DEK) were found only in intracellular lactate levels. Further pathway hits include β-catenin include glycolysis, glycosylation, TCA cycle/anaplerosis, NAD+ production, and creatine dynamics. Genes in these pathways epistatic to RON-DEK-β-catenin were used to define a gene signature that prognosticates breast cancer patient survival and response to chemotherapy.Conclusions:?The RON-DEK-β-catenin axis regulates the numerous metabolic pathways with significant associations to breast cancer patient outcomes.