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Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1
Medard F M van den Broek1, Bernadette P M van Nesselrooij2, Carolina R C Pieterman1
1Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Context:
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs.
Objective:
To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands.
Methods:
All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared.
Results:
A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results.
Conclusions:
These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.
Insights
Genetic anticipation may be occurring in Multiple Endocrine Neoplasia type 1 (MEN1) families, with earlier onset of tumors across generations. Further research is needed to confirm these findings for personalized screening.
Area of Science:
- Genetics and Hereditary Diseases
- Endocrinology
- Oncology
Background:
- Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant disorder.
- MEN1 is caused by mutations in the MEN1 gene, leading to various tumors including primary hyperparathyroidism, neuroendocrine tumors, and pituitary tumors.
- Understanding age-related penetrance is crucial for developing personalized screening strategies.
Purpose of the Study:
- To investigate the phenomenon of genetic anticipation in large Dutch MEN1 families.
- To determine if MEN1 manifestations occur at an earlier age in successive generations.
Main Methods:
- Identified 10 large Dutch MEN1 families with at least 10 affected members across two or more generations.
- Compared age at detection of MEN1-related manifestations (pHPT, dpNET, PIT, bp-NET) among generations.
- Utilized regression analyses adjusted for competing risks and surveillance effects.
Main Results:
- A total of 152 MEN1 patients were analyzed.
- Significant decrease in age at detection for primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, pituitary tumors, and bronchopulmonary neuroendocrine tumors in successive generations (P < 0.0001).
- Adjusted analyses confirmed the findings, suggesting genetic anticipation.
Conclusions:
- The study suggests the presence of genetic anticipation in MEN1.
- Results should be interpreted cautiously due to potential residual bias.
- Independent validation and further research into molecular mechanisms are recommended for personalized screening protocols.
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