Endocrine Abstracts

Background: The presence of a genotype-phenotype correlation in patients with MEN1 remains controversial with conflicting data from different centers. Furthermore, about 10-30% patients have genotype-negative (GN)-MEN1. Here, we evaluate the presence of genotype-phenotype correlation in our cohort of comprehensively phenotyped patients with MEN1. In addition, we compare the phenotype of GN-MEN1 and genotype-positive (GP)-MEN1 patients and investigate somatic mosaicism as a cause of GN-MEN1.

Methods: Index patients (first patient in kindred to be diagnosed with MEN1) or probands (first patient from kindred to be evaluated at our center) from kindreds with GP-MEN1 were identified. Germline variants in GP-MEN1 patients were categorized into high-impact (nonsense, frameshift, splice site, whole or partial gene deletion) or low-impact (missense or in-frame indels) groups. GN-MEN1 patients showed no mutations in MEN1 or other PHPT genes (CASR, RET, CDKN1B, CDC73, AIP, GNA11, AP2S1, GCM2). All patients underwent testing for tumor biomarkers, imaging and evaluation for Zollinger-Ellison syndrome (ZES). Whole exome sequencing was performed on multiple tumors from 13 GN-MEN1 patients.

Results: We identified 160 patients with GP-MEN1 (96 females) and 42 (31 females) with GN-MEN1. Among GP-MEN1, 97 had high impact and 34 had low-impact mutations. Mean age at last follow-up was 56 (±14) years for GN-MEN1 and 52 (±16) years for GP-MEN1 patients. All patients with high-impact mutations had PHPT (58% had recurrent disease), 70% had pituitary tumors (35% with macro-adenomas) and 63% developed GEP-NETs (24% with distant metastases). In comparison, 88% patients with low-impact mutations developed PHPT (48% with recurrent disease), 77% developed pituitary tumors (21% with macro-adenomas) and 75% developed GEP-NETs (24% with distant metastases). Among the GN-MEN1 patients, 38/42 developed PHPT - 3/38 (8%) had recurrent disease. In GP-MEN1, 103/107 developed PHPT - 62/103 (60%) with recurrent disease. Median age of index presentation with PHPT was significantly different between the two groups (27.5 years in GP-MEN1 vs 53 years in GN-MEN1, p<0.05). 33/42 GN-MEN1 patients had a pituitary adenoma (22/33 functioning – 9/22 prolactinomas; 8/22 GH-secreting). In comparison, 72/103 GP-MEN1 patients developed a pituitary adenoma (37 functioning – 30/37 prolactinomas, no GH-secreting tumors). In the GN-MEN1 group, 12/42 (29%) patients developed a gastro-entero-pancreatic (GEP)-NET. In comparison, 64/98 (65%) patients with GP-MEN1 had a GEP-NET. Somatic variants in MEN1, CDC73 or CDKI were observed in six tumors. However, these variants were not seen in a second tumor/s or germline DNA from the patient.

Conclusion: Patients with GP-MEN1 have distinct characteristics with younger age of onset, greater likelihood of recurrent PHPT and co-occurrence of GEP-NETs in comparison to GN-MEN1. No apparent correlation in phenotype between high-impact vs. low-impact mutations is noted. Our findings do not support somatic mosaicism as a cause of GN-MEN1.

Abstract ID 23684