No evidence of RET germline mutations in familial pituitary adenoma

Abstract

Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP ) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmutK) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*GOA and K1285GOA, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmutK and seven AIP mutation positive (AIPmutC) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (PZ0 . 05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas.

Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

“…However, pathogenic AIP and RET mutations that were introduced into cells did not impair the AIP-RET interaction. In addition, no RET mutations have been found in somatotropinomas or FIPA families (223,224). Survivin belongs to the family of inhibitors of apoptosis.…”

Multiple Endocrine Neoplasia 2a Presenting with Pheochromocytoma and Pituitary Macroadenoma

“…Approximately 5% of pituitary adenomas are hereditary in nature but not associated with MEN 1 or Carney complex [11]. A recent series evaluated patients with familial pituitary adenoma and screened for RET mutations and none were found [12]. Mutations of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP) are found in 20% of patients with familial pituitary adenoma [13].…”

“…Mutations of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP) are found in 20% of patients with familial pituitary adenoma [13]. AIP has been shown to have in vivo interaction with RET, though the precise role of this interaction is not completely characterized [12]. Vargiolu et al evaluated tissue from 28 nonfamilial pituitary adenomas for mutation of either AIP or RET and none were identified [14].…”

The Genetics of Pituitary Adenomas

“…To date, only few case reports have described patients with MEN2A/2B and PAs: GH-secreting (n = 1), ACTH-secreting (n = 1) and non-functioning (n = 1) adenomas [37][38][39]. Furthermore, RET gene mutations do not commonly present in patients with isolated sporadic or familial PAs, suggesting that it is a rare cause of pituitary adenomas [40][41][42].…”