title: 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.Conclusions:These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression.Clin Cancer Res; 23(7); 1841-51. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Wenya Linda
authors.initials: WL
authors.lastname: Bi
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Surgery, The University of Chicago, Chicago, Illinois.
authors.forename: Peleg
authors.initials: P
authors.lastname: Horowitz
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Noah F
authors.initials: NF
authors.lastname: Greenwald
authors.affiliation: Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital, Boston, Massachusetts.|Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.|The Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Malak
authors.initials: M
authors.lastname: Abedalthagafi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Agarwalla
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Wiliam J
authors.initials: WJ
authors.lastname: Gibson
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Uri
authors.initials: U
authors.lastname: Ben-David
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chevalier
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute of Harvard and MIT, Harvard Medical School, Boston, Massachusetts.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Carter
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Grace
authors.initials: G
authors.lastname: Tiao
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.|Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: Clinical Cytogenetics Laboratory, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ducar
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: MacConaill
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Laws
authors.affiliation: Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. idunn@partners.org Rameen_Beroukhim@dfci.harvard.edu.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. idunn@partners.org Rameen_Beroukhim@dfci.harvard.edu.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002877:Chromosomes, Human / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D000073359:Exome Sequencing