: Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours (PANETs) are rare, slow growing cancers that often present with local and distant metastasis upon detection. PANETS contain distinct karyotypes, epigenetic dysregulation, and recurrent mutations in MEN1, ATRX and DAXX (MAD+); however, the molecular basis of disease progression remains uncharacterized. We evaluated associations between aneuploidy and the MAD+ mutational state of 532 PANETs. Using this data, we propose an evolutionary model for a subset of aggressive PANETs that is initiated by mutation of MEN1, ATRX and DAXX, resulting in defects in centromere cohesion from ectopic CENP-A deposition that leads to selective loss of chromosomes and the LOH phenotype seen in late-stage metastatic PANETs.EGA study EGAS00001004239