Multiple endocrine neoplasia type 1: clinical correlates of MEN1 gene methylation

Multiple Endocrine Neoplasia Type 1 (MEN 1) has marked severity variation between individuals with the same mutation. To investigate any relationship between promoter methylation and clinical features, blood and tissue samples were collected from 16 16 members of the Tasman 1 MEN 1 kindred carrying a common splice site mutation and 7 patients with sporadic MEN 1. Methylation at 39 CpGs in the MEN1 promoter were assessed in formalin-fixed paraffin embedded parathyroid tissue. Clinical disease severity markers included age at first parathyroid operation, parathyroid hormone level and corrected serum calcium levels. Six patients with sporadic hyperparathyroidism were used for comparison.

Minimal methylation was observed in all patients across CpG sites 1 – 23. In contrast, hypermethylation was observed at CpG sites 24 – 31 in MEN 1 patients, a pattern not observed in patients with non-MEN 1 parathyroid disease. Mean methylation at sites 24 – 31 was significantly correlated with age at first parathyroid operation (r = 0.652, p = 0.041). A permutation test, utilising the mean correlation coefficient (r = -0.401) revealed a possible association between relative PHPT severity and methylation score for each significant CpG site (p = <0.103). This novel study reveals evidence supporting a possible association between altered MEN1 promoter methylation and clinical severity of disease.