Genetic Correlates of Malignant Behavior in Aggressive Pituitary Tumors

Rezumat

Abstract Objective Aggressive pituitary neuroendocrine tumors (PitNETs) that progress despite surgery, radiotherapy (RT), and medical therapy are heterogenous; only a subset exhibits overtly malignant behavior. We examined genetic determinants of metastatic behavior and poor prognosis. Design Retrospective genomic cohort study of 39 patients (62 tumor samples) with aggressive PitNETs. Methods Next-generation sequencing was performed using the MSK-IMPACT platform on a sequencing protocol. Genetic alterations were correlated with metastatic status, and progression-free and overall survival (PFS and OS) from first progression following RT. Results Cell-cycle alterations were found in 23.1% of patients and were more frequently identified in metastatic compared to non-metastatic tumors (42.1% vs 5.0%; OR=12.9; p=0.008). TP53, ATRX, DAXX, and/or SF3B1 alterations were associated with adverse clinical outcomes but did not differ by metastatic status (53% of metastatic vs 60% of non-metastatic tumors). Within the corticotroph lineage, gene-level alterations in TP53, ATRX, and/or DAXX captured corticotrophs with recurrent chromosomal loss-of-heterozygosity (rcLOH), and were associated with shorter PFS (10.1 vs 149.9 months; p=0.009) and OS (116.6 months vs not reached [NR]; p=0.022). A subset of corticotrophs lacking rcLOH harbored gain-of-function USP8 mutations and were associated with longer PFS (149.9 vs 11.5 months; p=0.022). In lactotroph PitNETs, TP53, ATRX, and/or SF3B1 mutations were associated with shorter PFS (4.6 vs 21.5 months; p=0.049). Conclusions Cell-cycle alterations were enriched in metastatic PitNETs and may contribute to metastatic dissemination. Next-generation sequencing segregates aggressive PitNETs into prognostic subgroups.