Recurrent somatic mutations in Ying Yang 1 (YY1) are found in a subgroup of sporadic insulinomas

Insulinomas represent the most common form of hormonally active neuroendocrine tumors of the pancreas. In the majority of cases their functional activity causes relevant morbidity with severe hypoglycemic episodes. Expression experiments led to the notion, that insulinomas have distinctively different features from other neuroendocrine tumors. Disease initiating mechanisms or genetic causes, however, are not well understood. Next generation sequencing techniques have allowed massive parallel identification of DNA alterations in numerous tumor entities in recent years. We applied this method to an initial cohort of 8 patients (5 females and 3 males) with sporadic insulinomas. Overall, 41 relevant somatic genetic alterations were detected, and a recurrent T372R mutation in YY1 (Ying Yang 1) was found in 2 different tumors. YY1 has been shown to be involved in cell regulatory processes. To confirm the relevance of this mutation, a total number of 47 insulinomas from three German centers (Düsseldorf, Marburg and München) were screened for this hotspot mutation, and were found positive in 13% (6/47 samples) of cases, which was much lower than described in a previous study. Interestingly, all affected patients were female (6/6, P = 0.04), and tended to be older compared to YY1 non-mutated cases (61.8 ± 13.0 vs. 47.6 ± 17.4 years of age; p = 0.06). However, other clinical parameters, including malignant or metastatic disease and severity of hyperinsulinism were not different between the two groups. In summary, we thus describe presence and prevalence of recurrent YY1 mutations in sporadic insulinomas for the first time in the Caucasian population.