Mutations in USP48 and BRAF genes contribute to the overproduction of adrenocorticotropin (ACTH) hormone by the pituitary gland and consequent development of Cushing’s disease, a study shows, linking these genes to the disease for a first time.
The study, “Identification of recurrent USP48 and BRAF mutations in Cushing’s disease,” published in the journal Nature Communications, also identified a possible treatment for patients with BRAF-related mutations.
Cushing’s disease is a condition characterized by excessive cortisol levels that, if left untreated, can lead to serious cardiovascular problems, infections, and mood disorders. It usually arises from benign pituitary tumors that produce too much of ACTH hormone, which in turn stimulates the adrenal glands to secrete cortisol.
It is still not clear why some people develop these tumors, but studies have pointed to mutations in the USP8 gene as a possible cause. They are present in 35%–62% of all tumor cases, and influence treatment response and long-term outcomes.
But major disease drivers in people whose tumors have no evidence of USP8 mutations are unknown. Recognizing this gap, researchers in China examined tumor tissue samples from 22 patients with pituitary ademonas but a normal USP8 gene.
Their analysis revealed four genes that were recurrently mutated, including two — BRAF and USP48 — never before reported in this disease setting. Then, looking at 91 samples from patients, researchers found BRAF mutations in 17% of cases and USP48 mutations in 23% of patients.
These mutations were also found in patients with USP8-mutant pituitary tumors, but at a much lower rate — 5.1% for BRAF and 1.2% for USP48 mutations.
However, mutations in these two genes were not seen in patients with pituitary tumors producing other hormones, suggesting they are “unique genetic signatures of [ACTH-producing] adenomas,” the researchers wrote.
The team also found that BRAF and USP48 mutations activate signaling pathways that lead to the production of proopiomelanocortin (POMC), which is the precursor of ACTH.
“ACTH overproduction is a hallmark of Cushing’s disease and appears to be frequently induced by mutations in genes that tightly regulate POMC gene transcription in the pathogenesis of this disease,” investigators wrote.
Patients with BRAF and USP48 mutations had significantly higher levels of midnight plasma ACTH and midnight serum cortisol, compared to patients without these mutations. Tumor size, however, was similar among the two groups.
Interestingly, the team found that the BRAF inhibitor Zelboraf (vemurafenib) effectively reduced ACTH production in cells from ACTH-producing pituitary tumors. Zelboraf, marketed by Genentech, is approved in the U.S. and Europe to treat cancers with BRAF mutations, and findings suggest it may be a good therapeutic candidate for some people with Cushing’s disease.
“The mutational status of BRAF, USP8, and USP48 in corticotroph adenomas may be used in the future to characterize the molecular subtypes and guide targeted molecular therapy,” the researchers suggested.