Large genomic aberrations in corticotropinomas are associated with greater aggressiveness.

Context: Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas shows higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined.

Objective: We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents.

Samples and Design: Paired germline and tumor DNA samples from 27 pediatric patients with Cushing Disease (CD), were subjected to whole exome sequencing (WES). Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological and biochemical data from the patients were collected and correlated with the results of the CNV analysis.

Results: Chromosomal instability, involving 23-59% of the tumor genome, was noted in 5 out of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size which was larger (median size 18 mm vs 5.5 mm, p= 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (p= 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability.

Conclusions: A sub-group of corticotropinomas demonstrate chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that an increased number of genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.