The Genomic Landscape of Sporadic Prolactinomas

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The Genomic Landscape of Sporadic Prolactinomas Sunita M. C. De Sousa 1,2,3 & Paul P. S. Wang 4 & Stephen Santoreneos 5 & Angeline Shen 6,7 & Christopher J. Yates 6,7 & Milena Babic 2 & Leila Eshraghi 2,4,8 & Jinghua Feng 4,8 & Barbara Koszyca 9 & Samuel Roberts-Thomson 10 & Andreas W. Schreiber 4,8,11 & David J. Torpy 1,3 & Hamish S. Scott 2,3,4,8

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the gene locus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However, none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor. Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation, larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing. Keywords Prolactinoma . Pituitary adenoma . Whole exome sequencing . Copynumbervariation . Loss ofheterozygosity . Driver mutation

Introduction The genetic basis of sporadic prolactinomas is currently unknown. This is in contrast to well-described somatic events in other pituitary tumors, namely: GNAS mutations in somatotrophinomas and occasional non-functioning pituitary

* Sunita M. C. De Sousa [email protected] 1

Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia

2

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and University of South Australia Alliance, Adelaide, Australia

3

School of Medicine, University of Adelaide, Adelaide, Australia

4

ACRF Cancer Genomics Facility, Centre for Cancer Biology, an SA Pathology and University of South Australia Alliance, Adelaide, Australia

5

Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, Australia

adenomas [1–3]; USP8 [3, 4] and rarely NR3C1 [3, 6] mutations in corticotrophinomas; and CTNNB1 (encoding βcatenin) and BRAF mutations in the vast majority of adamantinomatous and papillary craniopharyngiomas, respectively [5]. Some of these somatic events recapitulate multisy