【佳學基因檢測】NF1 患者錯義變異預測 ATM 在改變神經(jīng)纖維瘤起始中的作用

基因突變怎么治療秘決

課題調研《腫瘤突變基因檢測與個性化治療方案的制定》《Acta Neuropathol》在?2020 Jan;139(1):157-174發(fā)表了一篇題目為《NF1 患者錯義變異預測 ATM 在改變神經(jīng)纖維瘤起始中的作用》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Yanan Yu?,?Kwangmin Choi,?Jianqiang Wu,?Paul R Andreassen,?Phillip J Dexheimer,?Mehdi Keddache,?Hilde Brems,?Robert J Spinner,?Jose A Cancelas?,?Lisa J Martin,?Margaret R Wallace,?Eric Legius,?Kristine S Vogel,?Nancy Ratner?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容關鍵詞：

ATM, DNA損傷,基因組學,修飾基因,突變,神經(jīng)纖維瘤, 1型神經(jīng)纖維瘤病。

腫瘤靶向治療基因檢測臨床應用結果

在 1 型神經(jīng)纖維瘤病中，雪旺細胞 (SC) 中的 NF1 基因突變驅動良性叢狀神經(jīng)纖維瘤 (PNF)，并且沒有額外的 SC 變化解釋腫瘤數(shù)量的患者間差異。來自雙胞胎研究的證據(jù)表明，可變的表達能力可能是由未知的修飾基因引起的。來自相同切除的 PNF 的 SC 和成纖維細胞 DNA 的全外顯子組測序證實了雙等位基因 SC NF1 突變,非 NF1 體細胞 SC 變體是可變的并且以低讀取數(shù)存在。我們將頻繁的種系變異鑒定為可能的神經(jīng)纖維瘤修飾基因。攜帶變異的基因在另外兩個 NF1 患者隊列中通過變異負荷測試得到驗證。包括 CUBN、CELSR2、COL14A1、ATR 和 ATM 在內的基因在一些神經(jīng)纖維瘤中也顯示出基因表達下降。 ATM 相關的 DNA 修復缺陷也存在于具有 ATM 變體的神經(jīng)纖維瘤子集和一些神經(jīng)纖維瘤 SC 中。雜合 ATM G2023R 或純合 S707P 變體降低了異源細胞中 ATM 蛋白的表達。在小鼠中，遺傳的 Atm 雜合性促進了雪旺氏細胞前體的自我更新并增加了體內腫瘤的形成，這表明 ATM 變異有助于神經(jīng)纖維瘤的發(fā)生。我們確定了在普通人群中罕見的種系變異，在患有神經(jīng)纖維瘤的 NF1 患者中過多。 ATM 和其他已鑒定的基因是 PNF 發(fā)病機制的候選修飾物。

腫瘤發(fā)生與反復轉移國際數(shù)據(jù)庫描述：

In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.