Clinical Identification of Oncogenic Drivers and Copy-Number Alterations in Pituitary Tumors

Abstract

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone-secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials.

Figure 1.

Mutation burden in pituitary adenomas as stratified by tumor subtype. (a) Mutation count across pituitary tumor subtypes. (b) Mutation count in pituitary adenomas stratified by histopathologic criteria. MIB-high, >3%. (c) Mutation count among pituitary adenomas stratified by hormonal subtype of genes mutated in at least four patients grouped by gene families. (d) Cluster diagram of related pathways for genes mutated in at least three patients, as predicted by GeNets (each color represents a distinct cluster). *P < 0.05. FSH, follicle-stimulating hormone; n.s., not significant; PRL, prolactin.

Figure 2.

Chromosomal copy-number alterations in pituitary adenomas. (a) Comut plot of pituitary adenomas demonstrating the association between disrupted subtype and histopathologic criteria of interest. (b) Log-fold change (LFC) in read count across all chromosomes for a sample with a disrupted copy-number profile. (c) Log-fold change in read count across all chromosomes for a sample with a quiet copy-number profile. (d) Number of samples that were classified as disrupted or quiet stratified by functional status. (e) Number of samples that were classified as disrupted or quiet stratified by chromosome 1 loss. (f) Number of samples that were classified as disrupted or quiet stratified by atypical status. (g) Number of samples that were classified as disrupted or quiet stratified by MIB-1 classification. (h) Number of samples that were classified as disrupted or quiet stratified by recurrence status. (i) Number of samples that demonstrated either nuclear or membranous β-catenin staining. *P < 0.05. n.s., not significant.