RF27 | LBSUN361 Understanding The Genetics Of Multiple Endocrine Neoplasia Type 1: The Road Ahead

BACKGROUND: About 10-30% patients have genotype-negative (GN)-MEN1. Here, we compare our cohort of comprehensively phenotyped GN-MEN1 and genotype-positive (GP)-MEN1 patients. We also investigate somatic mosaicism as a cause of GN-MEN1. METHODS: GN-MEN1 patients showed no mutations in MEN1 or other primary hyperparathyroidism (PHPT) genes (CASR, RET, CDKN1B, CDC73, AIP, GNA11, AP2S1, GCM2) performed per clinical indication. Index patients (first patient in kindred to be diagnosed with MEN1) or probands (first patient in kindred to be evaluated at our center) from kindreds with GP-MEN1 were identified. 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. GP-MEN1 patients were also categorized into high-impact (nonsense, frameshift, splice site, whole or partial gene deletion) or low-impact (missense or in-frame indels) mutation-bearing groups. RESULTS: We identified 43 (31 females, 12 males) patients with GN-MEN1 and 160 (102 index, 58 probands) patients with GP-MEN1 (98 females, 62 males). 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. Among the GN-MEN1 patients, 38/42 developed PHPT - 3/38 (8%) had recurrent disease. In GP-MEN1, 144/149 developed PHPT - 83/144 (58%) with recurrent disease. Median age of index presentation with PHPT significantly differed between the groups (27.5 years in GP-MEN1 vs 53 years in GN-MEN1 (χ(2) (1)=5.5: p <0.05)). 33/42 GN-MEN1 patients had a pituitary adenoma (22/33 functioning - 9/22 prolactinomas; 8/22 GH-secreting). In comparison, 94/145 GP-MEN1 patients developed a pituitary adenoma (51 functioning - 37/51 prolactinomas, no GH-secreting tumors). In the GN-MEN1 group, 12/42 (29%) patients developed a gastro-entero-pancreatic (GEP)-NET. In comparison, 86/130 (66%) patients with GP-MEN1 had a GEP-NET. Somatic variants in MEN1, CDC73 or CDKI were observed in six tumors. However, these mutations were not seen in another tumor/s or germline DNA from the patient. All patients with high-impact mutations had PHPT (63% had recurrent disease), 70% had pituitary tumors (35% with macro-adenomas) and 61% developed GEP-NETs (29% with distant metastases). In comparison, 91% patients with low-impact mutations developed PHPT (41% with recurrent disease), 69% developed pituitary tumors (23% with macro-adenomas) and 65% developed GEP-NETs (35% with distant metastases). CONCLUSION: Patients with GP-MEN1 generally experience younger age of onset, greater likelihood of recurrent PHPT and co-occurrence of GEP-NETs in comparison to GN-MEN1. Our findings do not support somatic mosaicism as a cause of GN-MEN1. No apparent correlation in phenotype between high-impact vs. low-impact mutations is noted. Presentation: Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.