MON-330 - A Genomically Unstable Subset of Pituitary Adenomas Defined by ATRX Alteration

Background:
Pituitary adenomas exhibit substantial heterogeneity in clinical presentation and biological behavior, yet the genomic mechanisms driving tumor initiation and progression remain poorly defined. While many pituitary adenomas are genomically stable with minimal copy-number alterations, a subset displays extensive chromosomal instability and widespread copy-number variation. Despite the frequency of this instability, prior studies have not identified consistent driver events explaining why certain tumors acquire high copy-number burden. Alterations in chromatin remodeling genes involved in telomeric maintenance, such as ATRX, are established drivers of chromosomal instability in other cancers through alternative lengthening of telomeres (ALT), but their role in pituitary adenomas has not been systematically explored.

Methods:
We performed whole-exome sequencing with integrated clinical annotation in a cohort of 180 pituitary adenomas to evaluate the prevalence and clinical impact of ATRX alterations, including single-nucleotide variants, short insertions/deletions, and copy-number alterations (CNA). Genome-wide CNA burden was quantified, and clinical features, including demographics, pre-operative pituitary hormone profiles and Ki-67 index, were compared between ATRX-altered and unaltered tumors.

Results:
ATRX alterations were identified in 32 of 180 tumors (17.8%). ATRX-altered tumors demonstrated significantly increased genome-wide CNA burden compared with unaltered tumors (median fraction of genome altered 0.152 vs. 0.021; p = 3.2 × 10⁻⁶, FDR-corrected q < 0.001), along with higher loss of heterozygosity. Recurrent involvement of chromosome arms 4p, 4q, 6q, Xp, and Xq was significantly enriched in the altered group (all FDR-corrected q < 0.05), indicating a consistent pattern of structural genomic instability extending beyond the ATRX locus. Ki-67 labeling index, demographic variables, and pre-operative pituitary hormone profiles did not differ between groups. This analysis is limited by reliance on genomic alterations to define ATRX status; transcriptomic or protein-level assessment may reveal a different frequency of ATRX loss, particularly in cases with copy-number deletions.

Conclusions:
ATRX alterations define a distinct subset of pituitary adenomas characterized by widespread chromosomal instability, independent of proliferative index or endocrine phenotype. These findings implicate disruption of telomere-associated chromatin regulation as a previously underrecognized contributor to genomic instability in pituitary adenomas.

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