Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1

Abstract

Functional pancreatic neuroendocrine tumours (PNETs) are mainly represented by insulinoma, which secrete insulin independent of glucose and cause hypoglycaemia. The major genetic alterations in sporadic insulinomas are still unknown. Here we identify recurrent somatic T372R mutations in YY1 by whole exome sequencing of 10 sporadic insulinomas. Further screening in 103 additional insulinomas reveals this hotspot mutation in 30% (34/113) of all tumours. T372R mutation alters the expression of YY1 target genes in insulinomas. Clinically, the T372R mutation is associated with the later onset of tumours. Genotyping of YY1, a target of mTOR inhibitors, may contribute to medical treatment of insulinomas. Our findings highlight the importance of YY1 in pancreatic b-cells and may provide therapeutic targets for PNETs.

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

“…This also provides a resource to determine the genetic basis of the disease which may impact treatment as well as behavior. Somatic mutations in genes including MEN1, ATRX, DAXX as well as in mTOR signaling (Leotlela et al 2003) and in the zinc finger YY1 (Cao et al 2013) have been identified in pancreatic NETs while inactivation of CDKN1B (P27…”

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…These mutations were prevalent in PanNET cases with hereditary component where they serve as an alternative mechanism of telomere length maintenance in an exclusive manner to ALT associated with DAXX/ATRX loss. A missense mutation in a gene encoding H3 histone family 3A (H3F3A), also known as H3.3, was found in one insulinoma (1/10) (Cao et al 2013). H3.3 is important in chromatin modification, replication and repair of DNA, regulation of gene expression as well as maintenance of centromeres and telomeres.…”

“…Indeed, DNA methylation is associated with specific histone modifications, in particular with high levels of H3K9 three-methylation and absence of histone H3K4 threemethylation. Lately, aberrant levels of specific histone variants or mutations in genes encoding for histones themselves have been reported in several type of cancers including NET , Cao et al 2013, FernandezCuesta et al 2014.…”

“…T372R mutation increased the transcriptional activity of YY1 resulting in higher expression of its target genes like the mitochondrial genes IDH3A and UCP2 in mutated tumours (Cao et al 2013).…”

“…Mutations of PTEN were found in 7.3% of PanNET and more recently mutations in TSC2, 8.8%; PIK3CA, 1.4% were also described (Perren et al 2000. TP53 mutations are rare in PanNET Jiao et al 2011, Cao et al 2013, Francis et al 2013, Cancer Genome Atlas Research 2014, Fernandez-Cuesta et al 2014, Cromer et al 2015, Lichtenauer et al 2015, Witkiewicz et al 2015, Scarpa et al 2017.…”