Abstract
PurposeGermline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs).MethodsPathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC).ResultsIn total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA.ConclusionAlthough most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.
Highlights
Pituitary adenomas are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal hypersecretion and tumor mass effects
Thyroid carcinoma was diagnosed before the pituitary adenoma in five cases, from 1 to 18 years before their pituitary adenoma had been diagnosed
Classicalvariant papillary thyroid carcinoma (PTC) was reported in most patients (n = 9), following by follicular thyroid carcinoma (FTC) (n = 5) and FVPTC (n = 3)
Summary
Pituitary adenomas are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal hypersecretion and tumor mass effects. Germline mutations have been described in the arylhydrocarbon receptor interacting protein (AIP) gene in the setting of either familial isolated pituitary adenoma (FIPA) or in simplex, young-onset pituitary adenomas, such as pituitary gigantism [4,5,6]. It is postulated that in AIP-mutated pituitary adenomas, AIP loses its activity as a tumor suppressor, which is supported by the association of loss-of-function mutations and the presence of loss of heterozygosity (LOH) at the AIP locus in the pituitary adenoma. To date there is no strong evidence linking germline AIP mutations to other neuroendocrine neoplasms apart from the pituitary
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