EPCO-35. GENOMIC CHARACTERIZATION OF GROWTH HORMONE SECRETING PITUITARY ADENOMAS

Abstract BACKGROUND Pituitary adenomas (PAs) are the second most common brain tumors in adults with prevalence ranging from 80 to 100 per 100,000 individuals. Of these, 9% to 14% are growth hormone (GH)-secreting PAs. While recurrent somatic GNAS mutations are identified in approximately half of sporadic GH-secreting PAs, the remaining cases are not well-characterized. This study aims to expand the genomic profile of GH-secreting PAs and explore correlations between molecular and clinical features. METHODS Whole exome sequencing (WES) was performed on 19 tumors with matching blood samples from consenting patients, achieving mean coverages of 262.74X for tumor samples and 112.43X for blood samples. Somatic variants, including single nucleotide variants (SNVs), short insertions/deletions (INDELs), and copy number variations (CNVs), were identified, and analyzed using protocols established by our institution. Genomic instability was assessed by calculating the percentage of the genome displaying loss-of-heterozygosity (LOH). Clinical data were collected and analyzed to establish genomic correlations. RESULTS The cohort comprised 19 GH-secreting PAs, with a mean age of 46 years at surgery, and was predominantly female (78.9%). The cohort was enriched for macroadenomas, with a mean tumor size of 18.4 mm. WES revealed a mean somatic mutation count of 20.4 (range 7-79), with 47% of cases harboring recurrent GNAS mutations. The mean alteration by LOH across the cohort was 11.13% (range: 0-44.80%) and did not show a statistically significant difference between cases with GNAS mutations and GNAS-wildtype cases (7.71% vs. 14.21%, respectively). Chromosomes 3, 8, 16, 22q were frequently affected by CNV/LOH events. CONCLUSION Comprehensive genomic characterization, including assessment of genomic instability through CNV/LOH analysis, is critical for better understanding the pathogenesis of GH-secreting PAs. This study underscores the importance of detailed genomic profiling in larger cohorts for improving the diagnosis and management of these tumors.