Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues

Abstract

Objective: Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptorinteracting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment. Design and methods: Fifty patients with acromegaly (22 males/28 females, age 51G18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification. Results: Sequence changes of potential different significance that could be considered as mutations or variations of unknown significance (VUS) of the AIP gene were found in four patients (8%). In two cases, two different mutations previously described were found: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787C24COT in intron 5 and c.100-18COT in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment. Conclusions: AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.European Journal of Endocrinology 168 9-13

Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort

“…In patient 3, genetic sequencing showed her to be heterozygous for intronic variant c.100-18COT. Although this variant has been compared with SNP database and the pathogenic potential of this variant is unclear, in this case it may be pathological, as previously described (26). Patient 4 was found to be heterozygous for a missense variant c.47GOA, in exon 1 of AIP, a variant of uncertain pathogenic significance.…”

Ocena efektów leczenia analogami somatostatyny nieczynnych hormonalnie gruczolaków przysadki w porównaniu z akromegalią

“…), should be tested for AIP gene mutations because deletions of chromosome area 11q13 are often found [26].…”

Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma

“…Generally, somatotropinoma with AIP mutation showed aggressive phenotype and resistance to SSA therapy [24,25]. Interestingly, we found that E-cadherin expression was lost in tumor tissues of all cases with the AIP mutations, which may explain at least in part, the mechanism underlying the aggressive phenotype and resistance to SSA.…”