title: Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome.
abstract: OBJECTIVE
  Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing.
  
  
  METHODS
  Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.
  
  
  RESULTS
  We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors.
  
  
  CONCLUSIONS
  Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Laboratory of Endocrinology and MetabolismInstitute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Tingwei
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of PathologyRui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Dalong
authors.initials: D
authors.lastname: Song
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Luming
authors.initials: L
authors.lastname: Wu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Liwen
authors.initials: L
authors.lastname: Fan
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors.|Laboratory of Endocrinology and MetabolismInstitute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Key Laboratory for Endocrine Tumors caoyanan@vip.sina.com.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000182:ACTH Syndrome, Ectopic / Q000097:blood / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000097:blood / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013953:Thymus Neoplasms / Q000097:blood / Q000235:genetics*; D054462:p21-Activated Kinases / Q000235:genetics
chemical_list: D000324:Adrenocorticotropic Hormone; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)