Endocrinol Metab.  2014 Sep;29(3):270-279. 10.3803/EnM.2014.29.3.270.

Genetic and Epigenetic Analysis in Korean Patients with Multiple Endocrine Neoplasia Type 1

• Chung YJ
• Hwang S
• Jeong JJ
• Song SY
• Kim SH
• Rhee Y

• KMID: 2169463
• DOI: http://doi.org/10.3803/EnM.2014.29.3.270

Abstract

BACKGROUND
Multiple endocrine neoplasia type 1 (MEN1) is a familial syndrome characterized by the parathyroid, pancreas and pituitary tumors. Parathyroid tumors are the most common clinical manifestations, occurring in more than 90% of MEN1 patients. Heterozygous germline mutations of the MENIN gene underlie the tumorigenesis in MEN1 and epigenetic alterations along with germline mutations may contribute to tumorigenesis. Here, we investigated the associations between genotype and phenotype in Korean MEN1 patients.
METHODS
We analyzed medical records from 14 unrelated MEN1 patients who had newly confirmed MENIN germline mutations, together with 14 previous reports in Korea. Aberrant DNA methylations were also examined in MEN1-related parathyroid tumors using the Infinium HumanMethylation 450 BeadChip.
RESULTS
Total 28 germline mutations of MENIN were relatively highly concentrated in exons 7 and 8 compared to previous reports from Western countries. Six mutations (c.111dupT/p.S38Ffs*79, c.225_226insT/p.T76Yfs*41, c.383_398del16/p.S128Tfs*52, c.746dupT/p.H250Afs*20, c.1150G>T/p.E384*, and c.1508G>A/p.G503N) were newly found in the present study. Of interest, four patients (15%) showed unusual initial presentations and three patients were diagnosed incidentally at the general medical checkup. We also found three distinct sites in exon 2 of MENIN were significantly hypomethylated in the MEN1 parathyroid tumors, comparing correspondent blood samples.
CONCLUSION
We also have found a lack of genotype/phenotype correlation in Korean MEN1 patients. There were not a few unusual initial manifestations in MEN1 patients, thus, genetic testing for the MENIN germline mutations can provide important information for the better prognosis. Further studies are warranted to investigate altered DNA methylations in the MENIN gene involved in tumorigenesis.

Keyword

Germ-line mutation; DNA methylation; Multiple endocrine neoplasia type 1; Korea

MeSH Terms

Carcinogenesis
DNA Methylation
Epigenomics*
Exons
Genetic Testing
Genotype
Germ-Line Mutation
Humans
Korea
Medical Records
Multiple Endocrine Neoplasia Type 1*
Pancreas
Phenotype
Pituitary Neoplasms
Prognosis

Figure

• 

  Fig. 1 Summary data of germline mutations of MENIN in 28 unrelated patients with multiple endocrine neoplasia type 1 in Korea. The positions of the mutations in MENIN are illustrated above respective exons. ATG refers to the start codon; TGA refers to the stop codon. aMutations were reported as novel in Korea including the present study. Germline mutations (I to IX) that occur with a frequency >1.5% are shown and their respective frequencies (scale shown on the right lower) in the review are indicated by the vertical lines at lower part of the gene [3]. These germline mutations, which collectively represent 20.6% of all reported germline mutations, are: I, c.249_252del GTCT (4.5%); II, c.292C>T (1.5%); III, c.358_360delAAG (1.7%); IV, c.628_631delACAG (2.5%); V, c.784-9G>A (1.9%); VI, c.1243C >T (1.5%); VII, c.1378C>T (2.6%); VIII, c.1546delC (1.8%); IX, c.1546_1547insC (2.7%).

• 

  Fig. 2 Frequencies of the types of MENIN mutations detected in 28 unrelated patients with multiple endocrine neoplasia type 1. In-frame deletion/insertion was not detected. Gross deletion was not confirmed.

• 

  Fig. 3 First manifestations of multiple endocrine neoplasia type 1 (MEN1) in Korea. Among 27 symptomatic patients, hyperparathyroidism was documented in 10 patients (37%), pancreas tumors in 10 (37%), and pituitary tumors in three (11%). Four patients (15%) showed less common tumors associated with MEN1 as a first manifestation.

• 

  Fig. 4 Distinct methylation pattern of hereditary parathyroid tumors compared to respective blood controls (A) and methylation profile of the MENIN gene (B). (A) Heatmap of all differentially methylated genes showing distinct methylation patterns of multiple endocrine neoplasia type 1 (MEN1)-related parathyroid tumors. Heatmap color corresponds to the β-value of the measured CpG-sites. β Ranges from 0 (purely unmethylated, shown in pink) to 1 (purely methylated, shown in green). (B) In this line plot blood average β is indicated by a black line and the parathyroid tissue average β is indicated by a grey line. Significant methylation differences are confined to exon 2 of the MENIN gene: three hypomethylation sites (cg10879244, cg22897141, and cg22527280) are described in the grey box with black arrows. The samples for heatmap are indicated according to specimen (B=blood sample and P=parathyroid tumor); digits after the hyphen denote case numbers as shown in Table 1. DMR, differentially methylated regions.

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