title: Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.
abstract: Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.
authors: Departments of Genetics, Howard Hughes Medical Institute.
authors: M Kyle
authors: http://orcid.org/0000-0002-3711-8833
authors: MK
authors: Cromer
authors: Departments of Genetics, Howard Hughes Medical Institute.
authors: Murim
authors: M
authors: Choi
authors: Departments of Genetics, Howard Hughes Medical Institute.
authors: Carol
authors: C
authors: Nelson-Williams
authors: Surgery, Yale Endocrine Neoplasia Laboratory, Yale Cancer Center, and.
authors: Annabelle L
authors: AL
authors: Fonseca
authors: Surgery, Yale Endocrine Neoplasia Laboratory, Yale Cancer Center, and.
authors: John W
authors: JW
authors: Kunstman
authors: Surgery, Yale Endocrine Neoplasia Laboratory, Yale Cancer Center, and.
authors: Reju M
authors: RM
authors: Korah
authors: Departments of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510;
authors: John D
authors: JD
authors: Overton
authors: Departments of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510;
authors: Shrikant
authors: S
authors: Mane
authors: Pathology, and.
authors: Barton
authors: B
authors: Kenney
authors: Division of Endocrinology and Neag Cancer Center, University of Connecticut Health Center, Farmington, CT 06030; and.
authors: Carl D
authors: CD
authors: Malchoff
authors: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
authors: Peter
authors: P
authors: Stalberg
authors: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
authors: Göran
authors: G
authors: Akerström
authors: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
authors: Gunnar
authors: G
authors: Westin
authors: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
authors: Per
authors: P
authors: Hellman
authors: Surgery, Yale Endocrine Neoplasia Laboratory, Yale Cancer Center, and.
authors: Tobias
authors: T
authors: Carling
authors: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
authors: Peyman
authors: P
authors: Björklund
authors: Departments of Genetics, Howard Hughes Medical Institute, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510; Internal Medicine, richard.lifton@yale.edu.
authors: Richard P
authors: RP
authors: Lifton
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D015331:Cohort Studies; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology; D007340:Insulinoma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C480968:CACNA2D2 protein, human; D015220:Calcium Channels; D007328:Insulin; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; D002118:Calcium
keywords: YY1; adenylyl cyclase; cAMP; exome sequencing; insulinoma