title: Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients.
abstract: BACKGROUND
  Whole-exome sequencing studies have not established definitive somatic mutation patterns among patients with sporadic hyperparathyroidism (HPT). No sequencing has evaluated multiple endocrine neoplasia type 1 (MEN1)-related HPT. We sought to perform whole-exome sequencing in HPT patients to identify somatic mutations and associated biological pathways and tumorigenic networks.
  
  
  METHODS
  Whole-exome sequencing was performed on blood and tissue from HPT patients (MEN1 and sporadic) and somatic single nucleotide variants (SNVs) were identified. Stop-gain and stop-loss SNVs were analyzed with Ingenuity Pathways Analysis (IPA). Loss of heterozygosity (LOH) was also assessed.
  
  
  RESULTS
  Sequencing was performed on 4 MEN1 and 10 sporadic cases. Eighteen stop-gain/stop-loss SNV mutations were identified in 3 MEN1 patients. One complex network was identified on IPA: Cellular function and maintenance, tumor morphology, and cardiovascular disease (IPA score = 49). A nonsynonymous SNV of TP53 (lysine-to-glutamic acid change at codon 81) identified in a MEN1 patient was suggested to be a driver mutation (Cancer-specific High-throughput Annotation of Somatic Mutations; P = .002). All MEN1 and 3/10 sporadic specimens demonstrated LOH of chromosome 11.
  
  
  CONCLUSIONS
  Whole-exome sequencing revealed somatic mutations in MEN1 associated with a single tumorigenic network, whereas sporadic pathogenesis seemed to be more diverse. A somatic TP53 mutation was also identified. LOH of chromosome 11 was seen in all MEN1 and 3 of 10 sporadic patients.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Minerva Angélica
authors.initials: MA
authors.lastname: Romero Arenas
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Fowler
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: San Lucas
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Thereasa A
authors.initials: TA
authors.lastname: Rich
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Grubbs
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Paul
authors.initials: P
authors.lastname: Scheet
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Perrier
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: HZhao2@mdanderson.org.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D063646:Carcinogenesis / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics / Q000473:pathology; D010865:Pilot Projects; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D055815:Young Adult