Recurrent somatic mutation altering DNA-binding motif of transcription factor YY1 explains pathogenesis of insulin-producing adenomas. M. K. Cromer1,2, M. Choi1,2, C. Nelson-Williams1,2, A. L. Fonseca3, J. W. Kunstman3, R. M. Korah3, J. O. Overton1,4, S. Mane1,4, B. Kenney5, C. D. Malchoff6, P. Stalberg7, G. Akerström7, G. Westin7, P. Hellman7, T. Carling3, P. Björklund7, R. P. Lifton1,2,4,8 1) Department of Genetics, Yale University School of Medicine, New Haven, CT; 2) Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT; 3) Department of Surgery, Yale Endocrine Neoplasia Laboratory and Yale Cancer Center, Yale University School of Medicine, New Haven, CT; 4) Yale Center for Genome Analysis, Yale University, New Haven, CT; 5) Department of Pathology, Yale University School of Medicine, New Haven, CT; 6) Division of Endocrinology and Neag Cancer Center, University of Connecticut Health Center, Farmington, CT; 7) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 8) Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
Insulinomas are benign or malignant pancreatic tumors that inappropriately secrete insulin, producing hypoglycemia. Despite an average of less than 4 protein-altering somatic mutations per tumor, 11 of 33 benign insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor YY1. ChIP-Seq showed that this mutation, YY1T372R, changes the DNA motif bound by YY1. Gene expression analysis distinguished tumors with and without YY1T372R mutations and identified genes with new YY1 binding sites and significantly altered expression. These included two, ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca2+ channel pore-forming subunit), involved in key pathways regulating insulin secretion. Expression of these genes in the rat INS-1 cell line resulted in markedly increased insulin secretion. These findings implicate YY1T372R in insulinoma pathogenesis and intracellular Ca2+ as a common mechanism underlying endocrine neoplasias.
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