Landscape of Genomic Alterations in Pituitary Adenomas

Abstract

Purpose Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood. Experimental Design We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent. Results We identified mutations, insertions/deletions, and copy number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy-number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas. Conclusion These data indicate that sporadic pituitary adenomas have distinct copy number profiles that associate with hormonal and histologic subtypes and influence gene expression.

Case report: recurrent pituitary adenoma has increased load of somatic variants

“…The number of variants in primary PA is low, is consistent with the literature reported in other exome sequencing studies on PA [16,26] and corresponds to the mainly non-metastatic phenotype of PA. In spite of the relatively benign nature of PA, the regrowth in 2 years after the first surgery indicates the proliferative potential of the tumour cells in the studied patient.…”

“…All SNPs were in the heterozygous state. Three of the genes JPH2, OR5M1 and NPTXR have had a somatic variant (although different position) in previous PA exome sequencing studies in the literature [26,37], and further functional studies are needed to evaluate the role of these gene variants on pituitary cell functionality. Recurrence of deleterious rare SNVs across different PA sequencing studies could indicate that they could be part of Knudson's two hit hypothesis in PA, especially when taking into account other genetic and/ or environmental factors.…”

The Genetics of Pituitary Adenomas

“…Recently, Bi et al described a different profile of genomic aberrations: in a cohort of 42 PAs, a group of "disrupted" tumors, defined as large CNVs encompassing on average 39% of the tumor genome, were noted. These tumors were more likely to be functional adenomas, without evidence of more aggressive behavior [127,128]. Similar results were further described by other groups in GH-secreting tumors [129,130].…”

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…With regard to surgical management, it is important to distinguish between recurrence following non-optimal surgery and recurrence after surgery performed by an expert. The growth rate of pituitary tumours is influenced by patient-and tumourspecific characteristics; this intrinsic tumour heterogeneity determines the risk of recurrence and resistance to treatment (6,19,20).…”