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MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients
Joanne M de Laat1, Rob B van der Luijt2, Carolina R C Pieterman1
1Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Background:
Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up.
Methods:
This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population.
Results:
A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001).
Conclusions:
Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.
Insights
Multiple Endocrine Neoplasia type 1 (MEN1) patients without MEN1 gene mutations develop tumors later and have better survival than mutation-positive patients. These findings suggest mutation-negative cases may represent a distinct MEN1-like syndrome.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Multiple Endocrine Neoplasia type 1 (MEN1) is characterized by the development of specific endocrine tumors.
- A subset of MEN1 patients (10-30%) lack identifiable mutations in the MEN1 gene.
- The clinical characteristics and disease course of mutation-negative MEN1 patients remain poorly understood compared to mutation-positive individuals.
Purpose of the Study:
- To compare the clinical phenotype and long-term disease progression of MEN1 patients negative for MEN1 gene mutations with those who are mutation-positive.
- To investigate whether mutation-negative patients truly represent MEN1 or a different clinical entity.
- To evaluate differences in the age of onset, tumor development, and survival between these two groups.
Main Methods:
- A cohort study utilizing the comprehensive Dutch MEN1 database, encompassing over 90% of the national MEN1 population.
- Inclusion of 293 mutation-positive and 30 mutation-negative MEN1 patients.
- Long-term follow-up to assess clinical manifestations and survival outcomes.
Main Results:
- Mutation-negative MEN1 patients exhibited a significantly later median age at the first manifestation (46 years) compared to mutation-positive patients (33 years).
- A lower proportion of mutation-negative patients developed a third main MEN1 manifestation during follow-up (0% vs. 48.3%).
- Median survival was notably longer in mutation-negative patients (87.0 years) than in mutation-positive patients (73.0 years).
Conclusions:
- Significant differences in phenotype and clinical course exist between mutation-positive and mutation-negative MEN1 patients.
- Mutation-negative individuals present with MEN1 manifestations at an older age and experience a survival rate comparable to the general population.
- These disparities suggest that mutation-negative patients may have a MEN1-like syndrome or a sporadic occurrence of two neuroendocrine tumors, rather than classical MEN1.
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