TP53 Mutations Linked to Aggressive Cushing’s-causing Tumors
Researchers: Worse clinical outcomes, more interventions with mutated TP53
Cushing’s disease-causing tumors that harbor a mutation in the TP53 gene are generally larger, more invasive, and linked to poorer clinical outcomes, a new study reports.
The study, “TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome,” was published in Acta Neuropathologica Communications.
Cushing’s disease is caused by a tumor in the brain’s pituitary gland that causes it to produce and release high levels of a signaling molecule called ACTH, leading to increases of the stress hormone cortisol, which causes most Cushing’s symptoms.
These Cushing’s-causing pituitary tumors are called functional corticotroph tumors.
Like other types of tumors, these are marked by the presence of genetic mutations. A mutation in the gene USP8 is known to be a common driver of functional corticotroph tumors.
Across all types of cancer, TP53 is the single most frequently mutated gene. It provides instructions for making a protein that helps stop cell division when a cell’s DNA is damaged. When the gene is mutated, this protein can’t function properly, “taking off the brakes” of cell division and leading ultimately to uncontrolled cell growth.
Although generally common in malignant cancers, TP53 mutations have rarely been reported in functional corticotroph tumors.
Scientists in Germany looked for TP53 mutations in samples from 86 adults with functional corticotroph tumors, most of whom had been diagnosed with Cushing’s disease between 1994 and 2020.
Of the 86 tumors, 25 had mutations in the USP8 gene and none in TP53. Among the remaining 61 tumors, functionally relevant mutations in TP53 were identified in nine — a prevalence of 15%.
“Screening a large corticotroph tumor series revealed that TP53 mutations are more frequent than previously considered,” the researchers wrote.
Scientists also analyzed associations between TP53 mutation status and patient clinical outcomes.
Results showed people with TP53-mutant tumors tended to be diagnosed at an older age. They also underwent more surgeries and additional therapeutic procedures such as radiation and chemotherapy.
Tumors with TP53 mutations tended to be larger, though the difference was not statistically significant. They also were more likely to exhibit invasive behavior (growing and spreading beyond the pituitary gland) — as represented by higher Knosp grades — and generally showed signs of greater cell division.
“We do not have exact information on changes of tumor growth for the majority of our cases, but the higher number of surgical and radiation interventions, the higher Knosp grades, and the increased mortality rate indicate that patients with TP53 mutant tumors obviously follow a more aggressive disease course,” the researchers wrote.
Patients in the TP53-mutant group had higher disease-specific mortality and shorter survival times compared with those with USP8 mutations or with no mutations in either gene.
The 10-year survival rate was 27% for patients with TP53-mutant tumors, compared to 86% for those with USP8-mutant tumors and 100% for patients with no mutations in either gene.
“Our study provides evidence that patients with pathogenic [disease-causing] or function altering variants [in TP53] may require more intense treatment and extended follow-up,” the researchers wrote, noting the results support screening for TP53 in pituitary tumors without USP8 mutations.
The researchers said their study was limited by the small number of TP53-mutant tumors and the short patient follow-up times. They also noted that since the study intentionally focused on tumors without USP8 mutations, the overall prevalence of TP53 mutations in Cushing’s-causing tumors is likely lower than that identified in the study.
“Further work is needed to determine the potential use of TP53 status as a predictor of disease outcome,” the scientists wrote.