2. Academic Validation
  3. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

  • Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4062-7. doi: 10.1073/pnas.1503696112.
M Kyle Cromer 1,  Murim Choi 1,  Carol Nelson-Williams 1,  Annabelle L Fonseca 2,  John W Kunstman 2,  Reju M Korah 2,  John D Overton 3,  Shrikant Mane 3,  Barton Kenney 4,  Carl D Malchoff 5,  Peter Stalberg 6,  Göran Akerström 6,  Gunnar Westin 6,  Per Hellman 6,  Tobias Carling 2,  Peyman Björklund 6,  Richard P Lifton 7
Affiliations

Affiliations

  • 1 Departments of Genetics, Howard Hughes Medical Institute.
  • 2 Surgery, Yale Endocrine Neoplasia Laboratory, Yale Cancer Center, and.
  • 3 Departments of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510;
  • 4 Pathology, and.
  • 5 Division of Endocrinology and Neag Cancer Center, University of Connecticut Health Center, Farmington, CT 06030; and.
  • 6 Department of Surgical Sciences, Uppsala University, Uppsala, Sweden 751 05.
  • 7 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.
PMID: 25787250 DOI: 10.1073/pnas.1503696112
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.

Keywords

YY1; adenylyl cyclase; cAMP; exome sequencing; insulinoma.

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