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Frequency and consequence of the recurrent YY1 p.T372R mutation in sporadic insulinomas.

Extract: Pancreatic neuroendocrine tumors (PNETs/pNETs/p-NETs/PanNETs) are rare endocrine neoplasms that can be either functioning tumors that secrete hormones characteristic of their endocrine cell of origin, or nonfunctioning tumors. The most common functioning PNETs are the insulin-secreting b-cell tumors (insulinomas) that are mainly sporadic, but may also occur in 10% of patients with the hereditary tumor syndrome multiple endocrine neoplasia type 1 (MEN1) (OMIM ID: 131100). Patients with the MEN1 syndrome carry a heterozygous germline inactivating mutation in the MEN1 tumor suppressor gene and specific somatic loss of the normal MEN1 allele, leading to endocrine tumors mainly of the parathyroids, pituitary and pancreas (PNETs). Whole genome or whole exome sequencing (WES) of sporadic PNETs has revealed somatic MEN1 mutation in 37-44% of non-functioning PNETs (Jiao, et al. 2011; Scarpa, et al. 2017). However, four different WES studies of sporadic insulinomas found <2% with somatic MEN1 mutation, but rather they found a somatic heterozygous recurrent mutation in the Yin Yang 1 (YY1) gene (c.C1115G/p.T372R) in 30%, 33% and 13% of tumor samples (Cao, et al. 2013; Cromer, et al. 2015; Lichtenauer, et al. 2015; Wang, et al. 2017). Another study from India did not find this YY1 mutation in their insulinoma samples (Irshad, et al. 2017). To determine the frequency and consequence of the recurrent YY1 mutation we analyzed a cohort of 23 sporadic insulinomas.