...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways
【24h】

Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways

机译:胰腺肿瘤性囊肿的全外显子测序揭示泛素依赖性途径组分中的反复突变

获取原文
获取原文并翻译 | 示例
           

摘要

More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucin-ous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 + 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel-Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.
机译:超过2%的成年人患有胰腺囊肿,其中一部分进展为侵袭性损害,并具有致命后果。为了评估胰腺肿瘤性囊肿的基因组格局,我们确定了每种主要肿瘤性囊肿类型(浆液性囊腺瘤(SCA),导管内乳头状黏液性肿瘤(8))的八个手术切除的囊肿的肿瘤上皮中DNA的外显子序列。 IPMN),粘液性囊性肿瘤(MCN)和实体假乳头状肿瘤(SPN)。 SPN是低度恶性肿瘤,IPMN和MCN(而非SCA)具有发展为癌症的能力。我们发现每个肿瘤的SCA,IPMN,MCN和SPN分别包含10±4.6、27±12、16 + 7.6和2.9±2.1的体细胞突变。在鉴定出的突变中,E3泛素连接酶成分特别值得注意。八个SCA中有四个包含von Hippel-Lindau基因(VHL)的突变,该基因是VHL泛素连接酶复合物的关键组成部分,以前与肾细胞癌,SCA和其他肿瘤有关。八个IPMN中的六个和八个MCN中的三个具有RNF43突变,该基因编码具有内在E3泛素连接酶活性的蛋白,以前从未在任何人类癌症中发现过这种基因改变。 RNF43中失活突变的优势明确将其确立为IPMN和MCN的抑制剂。 SPN几乎没有遗传改变,但总是含有CTNNB1突变,先前已证明可抑制E3泛素连接酶降解编码蛋白(β-连环蛋白)。这些结果突出了泛素连接酶在这些肿瘤中的重要作用,并对囊性肿瘤患者的诊断和治疗具有重要意义。

著录项

  • 来源
  • 作者单位

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Departments of Pathology;

    Departments of Pathology;

    Departments of Pathology;

    Departments of Pathology;

    Departments of Pathology;

    Departments of Pathology,Medicine and Surgery;

    Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;

    Medicine and Surgery;

    Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;

    Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;

    Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231;

    Department of Pathology, Emory University, Atlanta, GA 30322;

    Departments of Pathology;

    Department of Pathology, University Medical Center of Utrecht, 3508 GA Utrecht The Netherlands;

    Departments of Pathology;

    Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Department of Biomedical Engineering, Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD;

    Department of Biomedical Engineering, Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

    Departments of Pathology;

    Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号