Genotype-phenotype correlation in multiple endocrine neoplasia type 1

Abstract

BACKGROUNDAmong patients with multiple endocrine neoplasia type 1 (MEN1), 80% develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom 15%-25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker, as it remains constant during life. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥2 primary endocrine tumors (pituitary, parathyroid, and pancreas) or ≥1 primary endocrine tumor with a positive family history. From 10% to 30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants.METHODSThis was a retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977 to 2022.RESULTSCompared with patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs, and angiofibromas or collagenomas. We propose a weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 had a reduced risk of distant metastases.CONCLUSIONThe clinical course of genotype-negative MEN1 is distinct from genotype-positive disease, raising uncertainty about the benefits of lifetime surveillance in patients with genotype-negative disease. MEN1 mosaicism is rare.TRIAL REGISTRATION ClinicalTrials.gov NCT04969926FUNDINGIntramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH (ZIA DK043006-46).

Keywords: Calcium; Diagnostic imaging; Endocrinology; Genetics; Molecular diagnosis; Oncology.

Figure 1. Study schematic.

Study schematic for design, sample selection, and study population.

Figure 2. MEN1 gene schematic with variants noted in our cohort.

Figure showing the number of unique variants, number of index patients or probands with the variant, and variant types found on each exon identified in the study. There were 5 whole/partial gene deletions not shown in the figure. The coding region for MEN1 includes exons 2 through 10 and encodes the protein menin. The gene contains 2 nuclear localization signals (NLSs), NLS1 (amino acids 479–497) and NLS2 (amino acids 588–608), and 1 accessory NLS (aNLS, amino acids 546–572). It interacts with proteins JunD (menin amino acids 1–40, 139–242, and 323–428) (51), checkpoint kinase 1 (CHES1, menin amino acids 428–610) (52), Smad3 (menin amino acids 1–40, 278–477) (53), NF-κB (menin amino acids 276–479) (51), and mixed lineage leukemia protein-1 (MLL1, menin amino acids 1–350) at sites shown in the figure in yellow. Exon 1 is noncoding and includes residues c.–110 to c.–24; exon 2 (c.-23 to 445); exon 3 (c.446 to 654); exon 4 (c.655 to 783); exon 5 (c.784 to 824); exon 6 (c.825 to 912); exon 7 (c.913 to 1049); exon 8 (c.1050 to 1185); exon 9 (c.1186 to 1350); and exon 10 (c.1351 to 1833). Noncoding regions in exon 2 and 10 are indicated. Variant nomenclature is as per MEN1 sequence encoding the 610–amino acid version of menin, accession number NM_130799.2. See Supplemental Table 2 for consequences of novel variants observed in the cohort. Created with BioRender.com.

Figure 3. Age-related penetrance of primary endocrine tumors by genotype status.

Kaplan-Meier curve relating age at diagnosis on the x axis to cumulative occurrence of first (A), second (B), and third (C) primary MEN1-related endocrine tumor (irrespective of the site of the primary tumor) on the y axis for both genotype-positive and genotype-negative groups. Each step down on the curve refers to a diagnosis of the respective tumor within the group. Crosses refer to age at last follow-up of a patient with no diagnosis of the relevant tumor in the respective group. The number of individuals in each category at each time point is depicted in the table below the curve. P value denotes statistical comparison for significant differences between the groups.

Figure 4. Age-related penetrance of individual primary and nonprimary manifestations by genotype-status.

Kaplan-Meier curve relating age at diagnosis on the x axis to cumulative occurrence of primary pituitary adenomas (A), hyperparathyroidism (B), dpNETs (C), and nonprimary manifestations such as lung NET or thymic or adrenal tumors (D) on the y axis for both genotype-positive and genotype-negative group of patients. Each step down on the curve refers to a diagnosis of the respective tumor within the cohort. Crosses refer to age at last follow-up of a patient with no diagnosis of the relevant tumor in the respective curve. The number of individuals in each category at each time point is depicted in the table below the curve. P value denotes statistical comparison for significant differences between genotype-positive and genotype-negative groups.