Urs D Lichtenauer1, Guido Di Dalmazi, Emily P Slater, Thomas Wieland, Anne Kuebart, Anett Schmittfull, Thomas Schwarzmayr, Susanne Diener, Dominik Wiese, Wolfgang E Thasler, Martin Reincke, Thomas Meitinger, Matthias Schott, Martin Fassnacht, Detlef K Bartsch, Tim M Strom, Felix Beuschlein. 1. Medizinische Klinik und Poliklinik IV (U.D.L., G.D.D., M.R., F.B.), Klinikum der Universität München, 80336 Munich, Germany; Department of Visceral, Thoracic, and Vascular Surgery (E.P.S., D.W., D.K.B.), University Hospital Giessen and Marburg GmbH, 35043 Marburg, Germany; Institute of Human Genetics (T.W., A.S., T.S., S.D., T.M., T.M.S.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Funktionsbereich Spezielle Endokrinologie (A.K., M.S.), Universitätsklinikum Düsseldorf, 40225 Düsseldorf Germany; Biobank (under the administration of the Human Tissue and Cell Research) Foundation (W.E.T.), Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Germany Institute of Human Genetics (T.M., T.M.S.), Technische Universität München, 81675 Munich, Germany; German Centre for Cardiovascular Research Partner Site (T.M., T.M.S.), Munich Heart Alliance, 80802 Munich, Germany; Department of Medicine I (M.F.), Endocrine and Diabetes Unit, University Hospital, University of Würzburg, 97080 Würzburg, Germany; and Comprehensive Cancer Center Mainfranken (M.F.), University of Würzburg, 97080 Würzburg, Germany.
Abstract
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.
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.
Authors: Vaishali I Parekh; Sita D Modali; James Welch; William F Simonds; Lee S Weinstein; Electron Kebebew; Sunita K Agarwal Journal: Endocr Relat Cancer Date: 2018-02-21 Impact factor: 5.678