Genetic and Epigenetic Alterations between Pituitary Adenoma and Pituitary Carcinoma

Introduction: Pituitary carcinoma is a rare, but poorly understood malignancy that can be difficult to diagnose and treat. Mortality is high and conventional therapies, such as temozolomide, have varying effect. Similarly, the genetics of tumor progression from pituitary adenoma to carcinoma is not well understood. This study investigates the epigenomic characteristics affecting these tumor types and affecting gene expression.

Methods: Three pituitary carcinoma patients were identified and case-matched non-invasive and invasive pituitary adenoma were selected for comparison. Individual patients receiving elective surgery with adenoma, invasive recurrent lesions and respective carcinoma were assessed for each patient. Whole exome genome sequencing, single nucleotide polymorphism (SNP6.0) array analysis, methylation 450K array analysis, and RNA next generation deep sequencing analysis was performed on these specimens.

Results: Genomic mutation analysis of these specimen identified significantly higher mutation frequency in the carcinoma samples compared with both adenoma groups. Furthermore, epigenomic methylation analysis identified differences between each group. Interestingly, there was more variance of methylation within the typical adenoma group compared with the invasive and carcinoma groups. Subgroup analysis identified two distinct genetic groups: group 1 had progressive hypomethylation comparing non-invasive, invasive and carcinoma tumors and group 2 had progressive hypermethylation. Additionally, there were “invasion specific” methylated groups without significant difference between invasive adenomas and carcinomas. Interestingly, many of the candidate genes demonstrating such variance included structural proteins with particular emphasis on the matrix metalloproteinase system (e.g., HSPG2, LVRN, GLT25D2 and ECE2) and proto-oncogenes (e.g., GATA1 and VSIG8). The major methylation patterns between invasive adenomas and pituitary carcinomas were quite similar in reference to typical adenomas suggesting the progression from the original adenoma.

Conclusions: Epigenetic regulation in the setting of tumor oncogenesis has recently demonstrated increased importance, particularly with genetic regulation. This study identifies methylation pattern variations between pituitary adenoma tumor types. Such data will be helpful to better understand the pathogenesis of this rare cancer and potentially identify novel genetic and modulatory therapeutic agents for pituitary carcinoma.