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Mutations in patients with MEN1 increased risk for malignancy, death
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Patients with multiple endocrine neoplasia type 1 who have mutations leading to a loss of interaction with certain domain codons may be at higher risk for malignancy and death based on disease process, according to research published in The Journal of Clinical Endocrinology & Metabolism.
With an aggressive course of disease, multiple endocrine neoplasia type 1 (MEN1) patients with a loss of interaction (LOI) with checkpoint suppressor 1 (CHES1) codons (428–610) are more likely to develop pancreatic neuroendocrine neoplasias (pNENs) and die of the disease, researchers found.
“This analysis reveals for the first time that patients with mutations affecting the CHES1-interacting domain as compared with patients with mutations affecting the other domains … had significantly higher rates of functioning pNENs, malignant pNENs, aggressive pNENs with the development of distant metastasis, and pNEN-related deaths, respectively,” the researchers wrote.
Detlef K. Bartsch, MD, of Philipps University Marburg, Germany, and colleagues evaluated the associations between MEN1 mutations in various interacting domains of the encoded Menin protein and the phenotype of pNENs in 71 genetically confirmed patients.
The researchers retrospectively analyzed patient characteristics and clinical phenotype of pNENs regarding both the mutation type and location in Menin from a prospectively collected cohort.
At a median follow-up of 134 months, 67 patients (93%) developed pNENs.
Mutations leading to LOI with CHES1 domain codons (428–610) vs. mutations leading to LOI with other domains showed higher rates of functioning pNENs (70% vs. 34%), malignant pNENs (59% vs. 16%) and aggressive pNENs (37% vs. 9%).
Further, patients with LOI with CHES1 also had higher rates of pNEN-related mortality vs. other domains (20% vs. 4.5%). No associations were observed between gender, age and blood types and the phenotype of pNENs.
“At the molecular level, loss of function of CHES1 may lead to additional mutations by impairing DNA-repair mechanism that potentially accelerate cell division,” the researchers wrote. “Through these mechanisms, LOI with CHES1 may promote a more aggressive phenotype.”
Although these molecular mechanisms were not analyzed and remain unclear, the researchers noted identifying such mutations could be relevant in assessing disease course and considering surgery if reliable indication for malignant and aggressive course of MEN1-pNENs is found.
Disclosure: The researchers report no relevant financial disclosures.
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