Using exome and targeted sequencing, researchers have identified identical somatic mutations in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1) in 14 of 43 insulinomas. The 372T>R substitution resulted in mutated YY1 binding a different DNA motif to wild-type YY1, which considerably alters gene expression. In tumours that contained this mutated form of YY1, expression of ADCY1 and CACNA2D2 was increased. The products of these genes are involved in key pathways (cAMP and Ca2+ signalling pathways) that regulate insulin secretion. Increased expression of ADCY1 and CACNA2D2 leads to increased insulin secretion via activation of these signalling pathways. The 372T>R mutation was not found in pancreatic tumours that do not secrete insulin, suggesting that the mutation is specific to insulinomas.
References
Cromer, M. K. et al. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc. Natl Acad. Sci. USA 10.1073/pnas.1503696112
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Genetic changes underlying insulinomas revealed. Nat Rev Endocrinol 11, 318 (2015). https://doi.org/10.1038/nrendo.2015.55
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DOI: https://doi.org/10.1038/nrendo.2015.55