新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 细胞生物学 » 全外显子测序发现胰腺癌新治疗靶点

全外显子测序发现胰腺癌新治疗靶点

来源:生物谷 2015-04-10 21:38

                                                             

    
2015年4月10日讯 /生物谷BIOON/ --近日,国际学术期刊nature communication在线发表了美国科学家的一项最新研究进展,他们对109名胰腺导管腺癌(PDA)病人进行了全外显子测序,发现了PDA中的基因突变多样性,并且为发现PDA治疗靶点提供了重要信息。
 
胰腺导管腺癌是一种预后效果非常差的恶性疾病,需要深入了解该疾病的病因并开发靶向治疗策略。由于PDA肿瘤中存在大量基质细胞和炎症细胞,因此对来自于病人的肿瘤样本进行肿瘤细胞测序存在很大障碍,难以获得高质量数据。
 
在该项研究中,研究人员为方便检测基因突变,同时移除非肿瘤性组织的污染,他们利用显微切割的方法将癌症患者的肿瘤组织进行了异种移植并建立了细胞系。随后对109例进行过显微切割的PDA病例进行了全外显子测序,经过显微切割操作后,肿瘤细胞得到富集并增强了对基因突变的检测。
 
研究人员通过分析发现导致PDA发生的病因事件与肿瘤突变谱具有明显相关性。拷贝数的改变会靶向多个肿瘤抑制/致癌基因位点,但是唯独MYC基因的扩增与PDA恶性程度和腺体亚型相关。他们还发现了PDA疾病中的多个新的突变基因,并且部分基因对于该疾病的预后效果具有重要影响。同时,在超过90%的病例中都可观察到KRAS突变但编码Q61密码子的基因与病人存活率增加具有特异性关联。癌基因BRAF突变与KRAS互相排斥,并且与vemurafenib治疗PDA模型的敏感性相关。研究人员还观察到Wnt信号通路,染色质重塑,Hedgehog通路,DNA修复和细胞周期进程中的相关基因都会发生高频率突变。
 
总的来说,这些结果描述了PDA疾病中新的基因多样性,为确定影响该疾病预后的因素,开发治疗方法提供了深入见解。(生物谷Bioon.com)
 
本文系生物谷原创编译整理。欢迎转载!转载请注明来源并附原文链接。更多资讯请下载生物谷资讯APP
 
 
 
Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
 
Agnieszka K. Witkiewicz,Elizabeth A. McMillan,Uthra Balaji,GuemHee Baek,Wan-Chi Lin,John Mansour,Mehri Mollaee,Kay-Uwe Wagner,Prasad Koduru,Adam Yopp,Michael A. Choti,Charles J. Yeo,Peter McCue,Michael A. White& Erik S. Knudsen
 
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAFmutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.
 
温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!



相关标签

最新会议 培训班 期刊库