Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas.

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.

• Authors: Urs D Lichtenauer, 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
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 5 Pg. E776-82 (May 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 25763608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• YY1 Transcription Factor
• YY1 protein, human

Topics

• Adult
• Aged
• Exome
• Female
• Humans
• Insulinoma (genetics, pathology)
• Male
• Middle Aged
• Mutation
• Pancreatic Neoplasms (genetics, pathology)
• YY1 Transcription Factor (genetics)