Multiple Endocrine Neoplasia Type 1 (MEN1) and Pituitary Adenoma Predisposition (PAP) in Northern Finland

Doctoral thesis English OPEN
Vierimaa, O. (Outi) (2008)
  • Publisher: University of Oulu
  • Journal: (eissn: 1796-2234)
  • Subject: genetic predisposition | multiple endocrine neoplasia type 1 | pituitary adenoma | primary hyperparathyroidism

Abstract Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome characterized by parathyroid, gastroenteropancreatic and pituitary neuroendocrine tumours. In Northern Finland, two founder mutations of the MEN1 gene (1466del12, 1657insC) accounting for the majority of the MEN1 cases, have common ancestors born in the 18th and 19th centuries, respectively. Three small clusters of familial pituitary adenoma have also been detected, two of which could be linked by genealogy to a common ancestral couple born in the 18th century. Clinical evaluation of 82 MEN1 mutation carriers showed that age was a risk factor for most of the MEN1-related manifestations. In the whole group, nonfunctional pancreatic tumour (NFPT) was more common in the frameshift/nonsense mutation carriers (odds ratio 3.26; 95% confidence interval 1.27–8.33, P = 0.014), whereas gastrinoma was more common in the in-frame/missense mutation carriers (OR 6.77, CI 1.31–35.0, P = 0.022). In the founder mutation carriers, the 1657insC mutation predicted the risk for NFPT (OR 3.56, CI 1.29–9.83, P = 0.015), while the 1466del12 mutation was associated with the risk for gastrinoma (OR 15.1, CI 1.73–131.9, P = 0.014). The mean ages at death of the 32 obligatory MEN1 founder mutation carriers born between 1728 and 1929 were compared to those of the 29 spouses and sex-matched life expectancy estimates derived from Finnish national statistics. The ages at death of the mutation carrier males (61.1 ± 12.0 years) and females (67.2 ± 10.7 years) did not differ from the control groups. PAP (pituitary adenoma predisposition) locus was mapped in the chromosome region 11q12–11q13 by whole-genome single-nucleotide polymorphism genotyping. Combining the linkage and the gene expression array data, AIP (aryl hydrocarbon receptor interacting protein) was chosen for sequencing. The nonsense mutation Q14X was identified in the affected (acromegaly, gigantism, prolactinoma) family members and in four other patients. Loss of heterozygosity was detected in pituitary adenomas of AIP mutation carriers. Mutation analysis of MEN1, HRPT2 (hyperparathyroidism 2), CASR (calcium-sensing receptor), CDKN1B (cyclin-dependent kinase inhibitor 1B) and AIP genes was performed in primary hyperparathyroidism patients with features of inherited predisposition. One out of 29 patients was found to have the 1466del12 mutation, while no mutations were detected in other genes.
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