LBMON174 Germline Molecular Genetics Of Pituitary Adenomas

Abstract

Abstract Introduction Pituitary adenomas (PA) are common. Considered to be mostly sporadic tumors for a long time, it has become clear over the last decade that a significant proportion of PA carry germline and/or somatic mutations. This study investigated the germline genetics of a large series of patients (pts) with PA using whole-exome sequencing (WES) and found a high rate of germline mutations in a number of genes including genes that were only known to be somatically mutated in PA. Methods After obtaining ethical approval and informed consent, we randomly included 128 pts (65 Females and 63 males, median age 33 years, IQ range 25-44) with PA (34 microadenomas and 94 macroadenomas). The diagnosis includes acromegaly in 16 pts, Cushing disease in 10 pts, prolactinomas in 50 pts, non-functioning PA in 37 pts, TSHoma in 1 pt, and gonadotrophinoma in 14 pts. None of those pts had a family history of PA or known syndromes. We isolated DNA from peripheral blood and performed WES using Illumina platform (Illumina NovaSeq 6000). For bioinformatics analysis, we removed all intronic and ncRNA variants and focused on exonic, exonic-splicing and splicing variants. We applied strict quality filters within the variant calling pipeline to exclude artifacts arising from the DNA sequencing and subsequent steps. We also removed all synonymous variants and variants marked as benign or likely benign by either Clinvar or ACMG Intervar databases. We followed the ACMG criteria in assigning pathogenicity levels to the variants. We focused on genes that were reported before to be involved in the germline, mosaic or somatic genetics of PA (AIP, GNAS, MEN1, DICER1, CDKN1B, PIK3CA, NF1, USP48 and USP8, GPR101, PRKARIA, PRKACB, MAX, CABLES1, SF3B1 and the SDHx group). Results We found 35 different variants in the PA-associated genes in 60 pts (46.9%). Some of these variants occurred in more than one patient with a total number of occurrences of 80. Most of these variants are mono-allelic (96.25%). These variants were found in the following genes: GNAS (10 variants in 39 pts), AIP (one variant in 1 patient), CDKN1B (2 variants in 2 pts), DICER1 (1 variant in 1 patient), MEN1 (2 variants in 3 pts), NF1 (3 variants in 3 pts), PIK3CA (1 variant in 1 patient), SDHA (3 variants in 3 pts), SDHAF2 (2 variants in 5 pts), SDHB (4 variants in 3 pts), SDHD (3 variants in 3 pts), USP48 (2 variants in 8 pts) and USP8 (1 variant in 1 patient). These variants included missense, non-sense, and small indels. Conclusions Germline variants in genes previously reported to be associated with PA are common in apparently sporadic PA occurring in about 47% of cases. For the first time, we report a significant occurrence of germline variants in genes that were previously known to be only somatically mutated (e. g., USP8, USP48, GNAS). Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.