Novel Mutations involving SMARCB1, KRAS, SMAD4 and RAD5 heterozygous deletion in Pituitary Tumors

Introduction: Pituitary adenomas are the second most common brain tumors. There has been increasing enthusiasm for genomic sequencing and DNA methylation profile analysis to better understand these tumors. The clinical implications of their genomic and epigenomic landscape is not understood. We aimed to identify clinically significant molecular variants in pituitary adenomas.

Methods: Genomic analysis of resected pituitary tumor was performed on seventeen consecutive patients with eighteen pituitary resections. The median patient age was 56, with a female to male gender ratio of 3:1. Genomic DNA was extracted from macro dissection-enriched FFPE tissue sections (≥30% neoplastic content), followed by enrichment of target exons and introns by hybrid-capture, sequencing and variant analysis using the Jackson Laboratory ActionSeqTM 2.0 test, a targeted-enrichment exon sequencing assay. Subsequent genomic methylation profiling was completed for additional classification.

Results: Of eighteen total cases, four were found to have clinically significant mutations, including MSH2, RAD51, SMARCB1, BRAF, KRAS, and SMAD4. One case previously described as an atypical pituitary adenoma and subsequently as metastatic pituitary carcinoma after the development of thoracolumbar epidural metastasis, was found to have two variants within the SMARCB1 gene. Identification of SMARCB1 mutations prompted further analysis with methylation profiling, which confirmed this tumor was consistent with atypical teratoid rhabdoid tumor. Further, to our knowledge we observed the first cases of RAD51 heterozygous deletion and KRAS A146T in pituitary adenoma.

Conclusion : Genomic sequencing reveals that pituitary adenomas may have heterogenous mutation patterns that can potentially be leveraged for precision medicine treatment and prognosis. For tumor with atypical features, clinical methylation profiling is a useful adjunct for precision diagnosis and prognosis.