title: Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing.
abstract: Cervical small cell neuroendocrine tumors (CSCNETs) are rare, aggressive neuroendocrine tumors (NETs). Reliable diagnostic and prognostic CSCNET markers are lacking, making diagnosis and prognosis prediction difficult, and treatment strategies limited. Here we provide mutation profiles for five tumor-normal paired CSCNETs using whole exome sequencing (WES). We expanded our assessment of frequently mutated genes to include publicly available data from 55 small intestine neuroendocrine tumors, 10 pancreatic neuroendocrine tumors, 42 small cell lung cancers, six NET cell lines, and 188 cervical cancers, along with our five CSCNETs. We identified 1,968 somatic mutations, including 1,710 missense, 106 nonsense, 144 splice site, 4 lncRNA, 3 nonstop, and 1 start codon mutation. We assigned functions to the 114 most frequently mutated genes based on gene ontology. ATRX, ERBB4, and genes in the Akt/mTOR pathway were most frequently mutated. Positive cytoplasmic ERBB4 immunohistochemical staining was detected in all CSCNET tumors tested, but not in adjacent normal tissues. To our knowledge, this study is the first to utilize WES in matched CSCNET and normal tissues to identify somatic mutations. Further studies will improve our understanding of how ATRX and ERBB4 mutations and AKT/mTOR signaling promote CSCNET tumorigenesis, and may be leveraged in novel anti-cancer treatment strategies.
authors.affiliation: Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Research Institute for Veterinary Science BK21, Program for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Minhye
authors.initials: M
authors.lastname: Choi
authors.affiliation: Division of Molecular and Life Sciences, Hanyang University, Ansan 15588, Republic of Korea.|Division of Bio-Medical Informatics, Center for Genome Science, National Research Institute of Health, Centers for Disease Control and Prevention, Choongchung-Buk-do 28159, Republic of Korea.
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Ban
authors.affiliation: Life Science Solutions Group, Thermo Fisher Scientific Corporation, Seoul 06349, Republic of Korea.
authors.forename: Chang Hyeon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Bio-Medical IT Research Department, ETRI, Yusoeng-gu, Daejeon 34129, Republic of Korea.
authors.forename: Soojun
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: HanKyeom
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Division of Molecular and Life Sciences, Hanyang University, Ansan 15588, Republic of Korea.
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods*; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D066247:Receptor, ErbB-4 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D000073359:Exome Sequencing; D000075924:X-linked Nuclear Protein / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: AKT/mTOR; ATRX; ERBB4; cervical small cell neuroendocrine tumor; whole exome sequencing