Context: Insulinomas represent pancreatic neuroendocrine neoplasms that cause severe morbidity attributed to their often pronounced endocrine activity. Apart from hereditary forms such as multiple endocrine neoplasia type 1 (MEN-1), genetic causes for sporadic insulinoma development had remained obscure until recently. Applying next-generation sequencing methods, disease-causing genetic alterations have been identified in various endocrine tumors.
Objective and design: Paired tumor and blood DNA from eight patients with sporadic insulinomas (five females and two malignant tumors) were analyzed by whole-exome sequencing. After this initial analysis, Ying Yang 1 (YY1) mutation status was assessed in a larger cohort of 39 additional insulinomas (including eight malignant and one liver metastasis) from three German hospitals by targeted sequencing. The mutation status was correlated with various clinical parameters.
Results: A range of one to 12 somatic genetic variants were identified by exome sequencing. A recurrent somatic Thr372Arg YY1 point mutation was detected in two patients of the initial cohort and four patients of the second cohort (total, six of 47; 13%). The presence of the mutation was associated with a trend toward higher age (63.5 y; IQR, 48.0-74.0 vs 45.0 y; IQR, 33.0-63.0; P = .05), and all affected patients were females (six of six; P = .04). All other clinical parameters, including the presence of malignancy and metastatic spread, tumor localization, and hypoglycemic episodes were not different between YY1-mutated and nonmutated tumor carriers.
Conclusions: The somatic Thr372Arg YY1 mutation is a relevant finding in female patients with sporadic insulinomas. The prevalence of this mutation in this Caucasian population is considerably lower compared to that of a recently described Asian cohort.