title: MAPK activation and HRAS mutation identified in pituitary spindle cell oncocytoma.
abstract: Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Wenya Linda
authors.initials: WL
authors.lastname: Bi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Ramkissoon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Yun Jee
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Malak
authors.initials: M
authors.lastname: Abedalthagafi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knoff
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Agarwalla
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, USA.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Alexander
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Laws
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Pathology, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Pathology, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D004252:DNA Mutational Analysis; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008875:Middle Aged; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HRAS; MAPK; genomics; pituitary; spindle cell oncocytoma