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Genetic evaluation of pediatric pituitary adenomas and USP8-related genotype-phenotype correlations in Cushing's
Rida Zainab1, Sukhvir Kaur1, Justin Lack2
1Unit on Hypothalamic and Pituitary Disorders, Eunice Kennedy Shriver National Institute of Child Health, and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA.
Insights
Genetic defects were identified in 25.9% of pediatric pituitary adenomas (PAs). Somatic USP8 variants in Cushing's disease patients correlated with worse outcomes, highlighting the need for further research into pediatric PA genetics.
Area of Science:
- Pediatric Endocrinology
- Neuro-oncology
- Cancer Genetics
Background:
- Pituitary adenomas (PAs) are rare in children, with poorly understood causes.
- Genetic factors are increasingly recognized in PA development.
Purpose of the Study:
- To determine the frequency of genetic defects in pediatric PAs.
- To investigate genotype-phenotype correlations in these tumors.
Main Methods:
- Genetic analysis of germline and tumor DNA from 54 pediatric PA patients.
- Sequencing of genes associated with pituitary tumorigenesis.
Main Results:
- Pathogenic variants identified in 25.9% of patients (AIP, CDKN2A, GNAS, USP8, PRKAR1A, TP53, MEN1).
- Somatic USP8 variants in pediatric Cushing's disease linked to larger tumors, increased invasion, and poorer surgical outcomes.
Conclusions:
- Somatic USP8 variants are associated with aggressive disease in pediatric Cushing's disease.
- The genetic basis for most pediatric corticotroph PAs remains elusive, necessitating further investigation.
Purpose:
Pituitary adenomas (PAs) constitute a rare pediatric diagnosis and their pathogenetic mechanisms are not clearly understood. The aim of this study was to evaluate the prevalence of genetic defects in pediatric PAs through germline and tumor testing, and to describe genotype-phenotype correlations.
Methods:
Fifty-four pediatric patients with PAs and available germline and/or tumor samples were studied. Germline and/or tumor sequencing were reviewed for variants in genes previously associated with pituitary tumorigenesis.
Results:
Germline genetic testing revealed a pathogenic variant in AIP gene in 2 patients with growth hormone excess (GHE) and a likely pathogenic variant in CDKN2A in a patient with Cushing's disease (CD). Somatic gene sequencing identified pathogenic variants in GNAS in 4/7 patients (57.1%) with GHE. 6/38 patients (15.8%) with CD had pathogenic variants in USP8 gene, and in one tumor pathogenic variants in PRKAR1A, TP53 and MEN1 genes were identified. Overall, pathogenic/likely pathogenic germline or somatic variants were identified in 14/54 patients (25.9%). When evaluating the genotype-phenotype correlations in patients with CD, patients with somatic USP8 pathogenic variants had larger tumors (median size: 9.5 mm [6.5, 13.3] vs. 6 mm [4.0, 7.0], p = 0.048), trend towards higher incidence of cavernous sinus invasion (50% vs. 12.5%, p = 0.06), and higher risk of non-remission after surgery (33.3% vs. 0%, p = 0.021) compared to patients without USP8 variants.
Conclusions:
Somatic USP8 pathogenic variants correlate with worse tumor behavior and patient outcomes in pediatric-onset CD. Unlike GH-secreting PAs, the genetic basis of the majority of pediatric corticotroph PAs remains unclear. Further studies are needed to explore the genetic drivers of pediatric CD.
Gov Id:
NCT00001595, NCT03206099.
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