Endocrinol Metab.  2024 Dec;39(6):956-964. 10.3803/EnM.2024.2008.

Genetic Landscape and Clinical Manifestations of Multiple Endocrine Neoplasia Type 1 in a Korean Cohort: A Multicenter Retrospective Analysis

• Kim B
• Lee SH
• Ahn CH
• Jang HN
• Cho SI
• Lee JS
• Lee YM
• Kim SJ
• Sung TY
• Lee KE
• Lee W
• Koh JM
• Seong MW
• Kim JH

• KMID: 2562723
• DOI: http://doi.org/10.3803/EnM.2024.2008

Abstract

Background
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in multiple endocrine organs, caused by variants in the MEN1 gene. This study analyzed the clinical and genetic features of MEN1 in a Korean cohort, identifying prevalent manifestations and genetic variants, including novel variants.
Methods
This multicenter retrospective study reviewed the medical records of 117 MEN1 patients treated at three tertiary centers in Korea between January 2012 and September 2022. Patient demographics, tumor manifestations, outcomes, and MEN1 genetic testing results were collected. Variants were classified using American College of Medical Genetics and Genomics (ACMG) and French Oncogenetics Network of Neuroendocrine Tumors propositions (TENGEN) guidelines.
Results
A total of 117 patients were enrolled, including 55 familial cases, with a mean age at diagnosis of 37.4±15.3 years. Primary hyperparathyroidism was identified as the most common presentation (84.6%). The prevalence of gastroenteropancreatic neuroendocrine tumor and pituitary neuroendocrine tumor (PitNET) was 77.8% (n=91) and 56.4% (n=66), respectively. Genetic testing revealed 61 distinct MEN1 variants in 101 patients, with 18 being novel. Four variants were reclassified according to the TENGEN guidelines. Patients with truncating variants (n=72) exhibited a higher prevalence of PitNETs compared to those with non-truncating variants (n=25) (59.7% vs. 36.0%, P=0.040).
Conclusion
The association between truncating variants and an increased prevalence of PitNETs in MEN1 underscores the importance of genetic characterization in guiding the clinical management of this disease. Our study sheds light on the clinical and genetic characteristics of MEN1 among the Korean population.

Keyword

Multiple endocrine neoplasia; Multiple endocrine neoplasia type 1; Genotype; Phenotype; Variant; Multicenter; Korea

Figure

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  Fig. 1. Prevalence of the primary hyperparathyroidism, gastroenteropancreatic and pituitary neuroendocrine tumor triad among (A) the total multiple endocrine neoplasia type 1 (MEN1) cohort (n=117) and (B) the index cases (n=84).

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  Fig. 2. Distribution of multiple endocrine neoplasia type 1 (MEN1) variants in the study cohort. The number of patients with each variant is indicated by the number within each circle, as well as circle size. Red, frameshift; orange, nonsense; green, in frame deletion; blue, missense; purple, canonical splice site; pink, intronic; gray, large deletion.

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  Fig. 3. Frequency of the types of multiple endocrine neoplasia type 1 (MEN1) variants in the study cohort (n=61).

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Reference

1. Hu X, Guan J, Wang Y, Shi S, Song C, Li ZP, et al. A narrative review of multiple endocrine neoplasia syndromes: genetics, clinical features, imaging findings, and diagnosis. Ann Transl Med. 2021; 9:944.

2. McDonnell JE, Gild ML, Clifton-Bligh RJ, Robinson BG. Multiple endocrine neoplasia: an update. Intern Med J. 2019; 49:954–61.

3. Jamilloux Y, Favier J, Pertuit M, Delage-Corre M, Lopez S, Teissier MP, et al. A MEN1 syndrome with a paraganglioma. Eur J Hum Genet. 2014; 22:283–5.

4. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38:394–402.

5. Niederle B, Selberherr A, Bartsch DK, Brandi ML, Doherty GM, Falconi M, et al. Multiple endocrine neoplasia type 1 and the pancreas: diagnosis and treatment of functioning and non-functioning pancreatic and duodenal neuroendocrine neoplasia within the MEN1 syndrome: an international consensus statement. Neuroendocrinology. 2021; 111:609–30.

6. Lips CJ, Dreijerink KM, Hoopener JW. Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation. Clinics (Sao Paulo). 2012; 67 Suppl 1:49–56.

7. Lips CJ, Dreijerink KM, Links TP, Hoppener JW. Recent results of basic and clinical research in MEN1: opportunities to improve early detection and treatment. Expert Rev Endocrinol Metab. 2012; 7:331–44.

8. Al-Salameh A, Cadiot G, Calender A, Goudet P, Chanson P. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021; 17:207–24.

9. Turner JJ, Christie PT, Pearce SH, Turnpenny PD, Thakker RV. Diagnostic challenges due to phenocopies: lessons from multiple endocrine neoplasia type1 (MEN1). Hum Mutat. 2010; 31:E1089–101.

10. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012; 97:2990–3011.

11. Concolino P, Costella A, Capoluongo E. Multiple endocrine neoplasia type 1 (MEN1): an update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016; 209:36–41.

12. Romanet P, Odou MF, North MO, Saveanu A, Coppin L, Pasmant E, et al. Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. Hum Mutat. 2019; 40:661–74.

13. Chung YJ, Hwang S, Jeong JJ, Song SY, Kim SH, Rhee Y. Genetic and epigenetic analysis in Korean patients with multiple endocrine neoplasia type 1. Endocrinol Metab (Seoul). 2014; 29:270–9.

14. Kwon EB, Jeong HR, Shim YS, Lee HS, Hwang JS. Multiple endocrine neoplasia type 1 presenting as hypoglycemia due to insulinoma. J Korean Med Sci. 2016; 31:1003–6.

15. Yang MA, Lee WK, Shin HS, Park SH, Kim BS, Kim JW, et al. Neuroendocrine tumors in the stomach, duodenum, and pancreas accompanied by novel MEN1 gene mutation. Korean J Gastroenterol. 2017; 69:181–6.

16. Kim SE, Lee NY, Cho WK, Yim J, Lee JW, Kim M, et al. Adrenocortical carcinoma and a sporadic MEN1 mutation in a 3-year-old girl: a case report. Ann Pediatr Endocrinol Metab. 2022; 27:315–9.

17. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17:405–24.

18. Zhou X, Edmonson MN, Wilkinson MR, Patel A, Wu G, Liu Y, et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat Genet. 2016; 48:4–6.

19. Kim B, Kim MJ, Hur K, Jo SJ, Ko JM, Park SS, et al. Clinical and genetic profiling of nevoid basal cell carcinoma syndrome in Korean patients by whole-exome sequencing. Sci Rep. 2021; 11:1163.

20. Marini F, Carbonell Sala S, Falchetti A, Caramelli D, Brandi ML. The genetic ascertainment of multiple endocrine neoplasia type 1 syndrome by ancient DNA analysis. J Endocrinol Invest. 2008; 31:905–9.

21. Giusti F, Cianferotti L, Boaretto F, Cetani F, Cioppi F, Colao A, et al. Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database. Endocrine. 2017; 58:349–59.

22. Sakurai A, Suzuki S, Kosugi S, Okamoto T, Uchino S, Miya A, et al. Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clin Endocrinol (Oxf). 2012; 76:533–9.

23. Ye L, Wang W, Ospina NS, Jiang L, Christakis I, Lu J, et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: a single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf). 2017; 87:706–16.

24. Thevenon J, Bourredjem A, Faivre L, Cardot-Bauters C, Calender A, Murat A, et al. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’etude des Tumeurs Endocrines (GTE) cohort study. Hum Mol Genet. 2013; 22:1940–8.

25. Yoon E, Lee JK, Park TK, Chang SA, Huh J, Kim JW, et al. Experience of reassessing FBN1 variants of uncertain significance by gene-specific guidelines. J Med Genet. 2023; 61:57–60.

26. Coppin L, Giraud S, Pasmant E, Lagarde A, North MO, LeCollen L, et al. Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow-up and genetic counseling? Eur J Endocrinol. 2022; 187:K1–6.

27. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006; 103:15558–63.

28. Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple endocrine neoplasia type 1: latest insights. Endocr Rev. 2021; 42:133–70.

29. Soczomski P, Jurecka-Lubieniecka B, Rogozik N, Tukiendorf A, Jarzab B, Bednarczuk T. Multiple endocrine neoplasia type 1 in Poland: a two-centre experience. Endokrynol Pol. 2019; 70:385–91.

30. Marini F, Giusti F, Brandi ML. Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients. Orphanet J Rare Dis. 2018; 13:205.

31. Marini F, Giusti F, Fossi C, Cioppi F, Cianferotti L, Masi L, et al. Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. Endocrine. 2018; 62:215–33.

32. Leeuwaarde RS, Herder WW, Valk GD. The need for national registries for rare endocrine tumor syndromes. Endocrine. 2017; 58:205–6.