Annamária Kövesdi1,2; Miklós Tóth1; Henriett Butz2,8; Nikolette Szücs1; Beatrix Sármán1; Péter Pusztai1; Péter Reismann1; Anikó Somogyi1; Katalin Borka3; Annamária Erdei4; Veronika Deák5; Zsuzsanna Valkusz6; Péter Igaz1,7; Attila Patócs2,8 and Vince Kornél Grolmusz1,2
1 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, 1088, Budapest, Hungary
2 “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences – Semmelweis University, Szentkirályi utca 46, 1088, Budapest, Hungary
3 2nd Department of Pathology, Semmelweis University, Üllői út 93, 1091 Budapest, Hungary
41st Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary
5 Kaposi Mór County Hospital, Tallián Gy. ut 20-32, Kaposvár, Hungary
6 1st Department of Medicine, University of Szeged, Korányi fasor 8-10., 6720 Szeged, Hungary
7 MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences – Semmelweis University, Szentkirályi utca 46, 1088, Budapest, Hungary
8 Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary
Parathyroid, pituitary and gastroenteropancreatic neuroendocrine tumors (GEP-NET) are the major manifestations of multiple endocrine neoplasia type 1 (MEN1) syndrome, caused by dominantly inherited germline mutations of the MEN1 gene. Malignant GEP-NETs are associated with significantly increased risk of death. Mutation analysis enables early diagnosis and the possibility of increased identification even of asymptomatic tumors.
To identify MEN1 mutations in patients with clinical suspicion of MEN1 syndrome and to find clinical features predictive of a positive genetic test.
189 probands and relatives referred to our national reference center were consecutively enrolled in our study. Mutation screeening of the MEN1 gene by Sanger sequencing and assessment of clinical data were performed.. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases.
27 probands and 20 family members carried MEN1 mutations. Five mutations have not been described earlier. MEN1-positive patients developed MEN1 syndrome suspicion at significantly earlier age compared to non-carriers. GEP-NET occured significantly more frequently already at initial presentation, and it presented significantly earlier in mutation carriers compared to mutaton-negative patients. In addition, probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers.
GEP-NETs best predicted a positive MEN1 genetic test. MEN1 patients with high-impact mutations were more likely to develop GEP-NETs, revealing possibly important prognostic consequences.
Doctoral School of Clinical Medicine
Hormonal Regulations Program
Supervisor: Attila Patócs
E-mail address: firstname.lastname@example.org