A pooled analysis of studies and data from a single center in Brazil suggest that people with Cushing’s disease (CD) who carry USP8 mutations, its major genetic cause, have differing outcomes, including in disease recurrence after surgery, from those who do not.
But a robust and more certain analysis was hindered because the published studies lacked a common protocol for evaluating patients.
Researchers call for a joint effort in setting up larger studies and in creating standard protocols to provide more consistent information about the influence of USP8 mutations.
The study, “Cushing’s disease due to somatic USP8 mutations: a systematic review and meta-analysis,” was published in the journal Pituitary.
Cushing’s disease is caused by tumors in the pituitary gland that lead to excessive adrenocorticotropic hormone (ACTH) levels, so that the adrenal glands produce too much cortisol, a condition known as hypercortisolism.
Normally, these tumors are small, less than 10 mm in diameter, and called microcorticotropinomas (MICs). But in 7% to 20% of patients, tumors can grow larger and are referred to as macrocorticotropinomas (MACs).
Standard treatment is surgery to remove the pituitary tumor. Remission (disappearance) of hypercortisolism is 76% for MICs and 43% of MACs, with the condition coming back in 23% to 33% of all cases.
Recently, mutations in the USP8 gene were identified as a major genetic cause of Cushing’s disease. Many studies have confirmed the presence of such mutations in adenomas, but the frequency of USP8-mutated tumors and their correlation with clinical outcomes varies greatly between reports.
Few studies have looked at how USP8 mutations relate to the presence of MICs and MACs, the clinical presentation of patients, or their response to treatment.
Researchers with the Hospital das Clínicas of the University of São Paulo took two approaches in addressing this: they looked at the mutations and outcomes of 47 people with pituitary tumors referred to their hospital, and they did a pooled analysis of nine published studies that covered a total of 630 patients.
DNA sequencing analysis of tumor samples from Brazilian patients identified four different USP8 mutations — all previously described — in 11 out of 47 (23.4%) pituitary tumors. Eight were larger tumors, or MACs.
Urine cortisol levels were lower in patients with USP8 mutations compared to non-carriers.
In the pooled analysis of prior studies, there were 290 MICs, including 121 (41.7%) with USP8 mutations, and 238 MACs, of which 73 (30.6%) had USP8 mutations.
Taken together, the prevalence of such mutations were approximately 30%, with female patients having a higher prevalence.
Combining four prior studies with new data from the Brazilian center suggested that carriers of USP8 mutations had greater chances of achieving remission following surgery compared to those without the mutations.
But these data should be interpreted carefully, as patient outcomes varied considerably between studies.
“Our data, as well as the systematic retrospective review of Cushing’s disease series associated with USP8-mutated alleles showed us a heterogeneous finding among the series,” the researchers wrote.
Associations between USP8 mutations and clinical outcomes “were variable” and had “several drawbacks due to the lack of a systematic protocol to evaluate these patients,” they added.
The team calls on a task force to conduct future studies at multiple sites that are able to yield more consistent information about the influence of the primary genetic cause of Cushing’s disease.
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