High prevalence of deleterious germline variants in cancer risk genes among subjects with young-onset, sporadic pituitary macroadenomas

IntroductionPituitary adenomas/pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors, clinically affecting 1:1000 individuals and most cases remain genetically unexplained. Emerging research has highlighted the major contribution of germline pathogenic variants to tumorigenesis across many tissue types in young subjects . We investigated whether young-onset (<30 years old) pituitary macroadenomas that were negative for known genetic causes harbor pathogenic or likely pathogenic (P/LP) variants in cancer-risk genes. MethodsWe retrospectively analyzed 48 subjects (29 males; 96% GH- or PRL-secreting) with sporadic pituitary macroadenomas that were negative for known germline variants (AIP, MEN1, CDKN1B) or duplications (GPR101). Whole-exome sequencing (WES) was performed on germline DNA. Bioinformatics analysis including variant calling (for small variants and CNVs), annotation and variant prioritization were performed, using secondary analysis pipelines for WES data and AION predictor platform for tertiary analysis. Variants in established cancer-risk genes were prioritized. ResultsP/LP germline variants in cancer-risk genes were identified in 14.6% of subjects on ClinVar/ACMG criteria. This rose to 31.3% of subject with deleterious variants when additional in silico and AION predictor criteria were used. Genes included: BAP1, BRCA1, BUB1, ELAC2, FLCN, MCPH1, MSR1, MUTYH, PDE11A, POLE, POLG, PMS2, RAD51C, RECQL4, SDHA, SDHD, SEC23B, TMEM127, WRN. ConclusionsOur findings expand the spectrum of genes potentially associated with young-onset pituitary macroadenomas. The identification of a high rate of deleterious germline variants in cancer-risk genes in pituitary adenomas/PitNETs echoes similar findings in young patients across a wide range of tumors. These results may have relevance for genetic counseling and potentially could expand targeted management strategies in young patients with large pituitary tumors.