USP8 gene mutations found to cause 35% of pituitary adenomas
Targeting gene may be therapeutic approach for Cushing’s patients: Study
Mutations in the USP8 gene are found in 35% of the pituitary corticotroph adenomas that cause Cushing’s disease, and more commonly affect women than men, a review study found.
Thus, targeting the gene and epidermal growth factor receptor (EGFR) — whose levels are increased in patients with USP8 mutations — may be a promising therapeutic approach for these patients.
However, “more precise multicenter studies are required to yield more consistent information regarding the [association between clinical and genetic profiles] and to develop effective targeted therapies,” the researchers wrote.
The study, “Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing’s disease and a systematic review of the literature,” was published in the journal BMC Endocrine Disorders.
Researchers in Iran investigated gene mutations in 19 patients
Cushing’s disease is marked by high levels of the hormone cortisol due to a tumor, usually benign, in the brain’s pituitary gland, particularly functional corticotroph adenomas. These tumors produce abnormally high amounts of the adrenocorticotropic hormone (ACTH) that triggers the adrenal glands to produce cortisol.
“The majority of functional corticotroph adenomas (FCAs) are sporadic,” the researchers wrote, but several genes have been proposed to be associated with the development and progression of such tumors.
These include the USP8 gene, which provides instructions to produce an enzyme of the same name that’s involved in regulating cell growth. USP8 mutations were found to excessively activate the EGFR molecular pathway, ultimately leading to excessive cell growth, as well as ACTH and cortisol production.
This suggests that “USP8 and EGFR are promising biomarkers for prediction of [tumor] recurrence and can be used as targeted therapy,” the researchers wrote.
Now, researchers in Iran investigated USP8 gene mutations in 20 pituitary tumor samples from 19 Iranian patients with functional corticotroph adenomas who underwent transsphenoidal adenomectomy, a surgery to remove pituitary tumors, between 2011 and 2019. Transsphenoidal adenomectomy is the first-line treatment of Cushing’s disease.
The patients ranged in age from 17 to 65 and nearly two-thirds (63%, or 12 individuals) were women.
Genetic analysis found two different USP8 mutations in tumor samples from two female patients: c.2151_2157delCTCCTCC and c.2159C>G. The first is a deletion of seven nucleotides, the building blocks of DNA, while the second is a missense mutation, or one that causes a substitution of an amino acid — protein’s building blocks — in the USP8 enzyme.
These mutations, which affected the USP8 enzyme’s interaction with other proteins, were found only in tumor tissue.
All but two patients achieved complete disease remission. In these two individuals, who did not carry USP8 mutations, the tumors could not be completely removed, and the patients underwent radiotherapy after surgery. Also, three patients, one without and two with USP8 mutations, had a tumor recurrence after the initial remission after surgery.
The team then conducted a systematic review of studies published through September 2023 describing the frequency of USP8 mutations in Cushing’s, patient outcomes according to mutation status, and USP8/EGFR signaling as therapeutic targets.
The final analyses included 31 studies, and 35% of all included patients with functional corticotroph adenomas carried a USP8 mutation. The most common mutation was c.2159C>G (25%).
USP8 gene mutations seen more often in women, younger patients
In general, USP8 mutations were more commonly detected in female and younger patients. “More precise studies are required to better explain the age-sex distribution of USP8 variant in patients with [Cushing’s disease],” the researchers wrote.
However, results regarding hormonal patterns were not consistent. Some studies indicated that patients with USP8 mutations had higher ACTH and cortisol levels, while another study indicated these patients had lower ACTH.
There also were discrepancies in reports of tumor size and invasiveness, or the tumor’s ability to spread to other tissues, in patients with or without USP8 mutations. Most studies, however, seem to indicate that these mutations are associated with smaller, less invasive tumors.
Regarding clinical outcomes, most studies indicated USP8 mutations were linked to a higher rate of disease remission. Some studies reported a higher tumor recurrence rate with these mutations, and others did not show an association.
The review also found that, regarding treatment, studies in cellular models indicated that USP8-mutated tumors responded better to Signifor (pasireotide), a treatment approved for adults with Cushing’s disease in whom pituitary surgery cannot be performed or was ineffective.
“These evidences suggest that USP8 mutational status could be used as a marker of [Signifor] response in [Cushing’s disease],” the researchers wrote.
Also, in preclinical studies, treatment with either EGFR inhibitors or USP8 inhibitors showed promising results for treating Cushing’s disease. In particular, USP8 inhibitors reduced ACTH production and cell growth.
“Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the [association between clinical and genetic profiles] and to develop effective targeted therapies,” the researchers concluded.
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