J Korean Surg Soc.  2009 Jan;76(1):15-22. 10.4174/jkss.2009.76.1.15.

Somatic Mutational Analysis of MEN1 and Phenotypic Correlation in Sporadic Parathyroid Tumors

• Chae YS
• Kim HJ
• Kim SW
• Chang MC

• KMID: 2040599
• DOI: http://doi.org/10.4174/jkss.2009.76.1.15

Abstract

PURPOSE
MEN1 gene mutation causes multiple endocrine neoplasia type 1. It also suggests that somatic MEN1 gene mutation plays a role in sporadic endocrine tumor. In this study, we examined whether somatic mutations of MEN1 gene are responsible for sporadic parathyroid tumors and correlate with clinical manifestations of parathyroid tumors.
METHODS
Somatic mutation of MEN1 gene in the formalin-fixed, paraffin-embedded parathyroid tumor tissue from 8 adenomas, 2 carcinomas and 1 hyperplasia were analyzed by direct sequencing. Clinicopathological parameters were reviewed from medical records and compared with the mutational data.
RESULTS
Eight of eleven (73%) sporadic parathyroid tumors had somatic MEN1 mutations of 14 different types. In the 14 types, 13 were a point mutation which is composed of 8 missense mutations, 2 nonsense mutations and 3 silent mutations. One of 14 types is a frameshift deletion of 27 base pairs in exon 2. Somatic mutation was frequent in the exon 2 and exon 10. Four types of polymorphism were found. There was no correlation between the presence of mutations and clinicopathological phenotype of parathyroid tumors.
CONCLUSION
This result suggests that somatic mutation of MEN1 gene plays a definite role in sporadic parathyroid tumor formation.

Keyword

Parathyroid; MEN1; Sporadic; Somatic mutation

MeSH Terms

Adenoma
Base Pairing
Codon, Nonsense
Exons
Hyperplasia
Medical Records
Multiple Endocrine Neoplasia Type 1
Mutation, Missense
Phenotype
Point Mutation
Codon, Nonsense

Figure

• 

  Fig. 1 The agarose gel electrophoresis of exon 2B of MEN1 in case 1, 3, 4, 10 parathyroid tissue. The band of case 3 (arrow) was double.

• 

  Fig. 2 The direct sequencing result of lower part band of exon 2B of MEN1 in case 3 parathyroid tissue. The lower graph was normal wild type and the upper graph was mutated result. The underlined 27bp sequences of normal wild type were deleted.

• 

  Fig. 3 Schematic representation of genomic structure and position of mutations and polymorphisms in the MEN1 gene. The upper part was the mutation and the lower part was the polymorphism. The length of the vertical line indicates the frequency of mutations. The shaded areas of exon 1 and part of exon 2 and 10 are non-translated code.

Reference

1. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997. 276:404–407.

2. Thakker RV. Molecular genetics and patient management of multiple endocrine neoplasia type 1. Best Pract Res Clin Endocrinol Metab. 2001. 15:189–212.

3. Pannett AA, Thakker RV. Multiple endocrine neoplasia type 1. Endocr Relat Cancer. 1999. 6:449–473.

4. Farnebo F, Teh BT, Kytola S, Svensson A, Phelan C, Sandelin K, et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab. 1998. 83:2627–2630.

5. Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet. 1997. 16:375–378.

6. Park JH, Kim IJ, Kang HC, Lee SH, Shin Y, Kim KH, et al. Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders. Clin Genet. 2003. 64:48–53.

7. Park SE, Kang ES, Lee HJ, Kim SH, Do MY, Kang SA, et al. A case of multiple endocrine neoplasia type 1 with mutation in MENIN gene. J Korean Soc Endocrinol. 2005. 20:71–77.

8. Sung HY, Chun YJ, Lee H, Kwon BJ, Park KW, Lee JM, et al. A case of familial multiple endocrine neoplasia with MEN1 gene mutation. J Korean Soc Endocrinol. 2006. 21:560–566.

9. Lee KD, Kim JY, Mun HS, Choi SH, Lee HH, Choi YS, et al. Menin mutational analysis in a MEN I family. Korean J Otolaryngol - Head Neck Sur. 2005. 48:347–351.

10. Lee SW, Choi YS, Park YH, Oh KS, Shin JW, Kim IJ, et al. A case of multiple endocrine neoplasia associated with VIPoma. J Korean Soc Endocrinol. 2005. 20:64–70.

11. Jo YE, Choi YJ, Kim YK, Ahn SM, Jung SH, Kim HJ, et al. A case of familial multiple endocrine neoplasia type 1 with MEN1 gene mutation. J Korean Soc Endocrinol. 2007. 22:68–73.

12. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1,336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008. 29:22–32.

13. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab. 1996. 81:1736–1739.

14. Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery AL Jr, et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med. 1994. 330:757–761.

15. Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours and hirschsprung disease. Hum Mutat. 1997. 9:97–109.

16. Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008. 93:682–687.

17. Correa P, Lundgren E, Rastad J, akerstrom G, Westin G, Carling T. Multiple endocrine neoplasia type 1 polymorphism D418D is associated with sporadic primary hyperparathyroidism. Surgery. 2002. 132:450–455.

18. Recommendations including Nomenclature Guidelines. Human Genome Variation Society. http://www.hgvs.org/.

19. Uchino S, Noguchi S, Sato M, Yamashita H, Yamashita H, Watanabe S, et al. Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors. Cancer Res. 2000. 60:5553–5557.

20. Scarpelli D, D'Aloiso L, Arturi F, Scillitani A, Presta I, Bisceglia M, et al. Novel somatic MEN1 gene alterations in sporadic primary hyperparathyroidism and correlation with clinical characteristics. J Endocrinol Invest. 2004. 27:1015–1021.

21. Goebel SU, Heppner C, Burns AL, Marx SJ, Spiegel AM, Zhuang Z, et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. J Clin Endocrinol Metab. 2000. 85:116–123.