MAPK activation and HRAS mutation identified in pituitary spindle cell oncocytoma

// Michael B. Miller 1, * , Wenya Linda Bi 2, 3, 10 , * , Lori A. Ramkissoon 4 , Yun Jee Kang 4 , Malak Abedalthagafi 1 , David S. Knoff 4 , Pankaj K. Agarwalla 3, 5 , Patrick Y. Wen 4, 10 , David A. Reardon 4, 10 , Brian M. Alexander 6, 7, 10 , Edward R. Laws Jr. 2, 10 , Ian F. Dunn 2, 10 , Rameen Beroukhim 3, 4, 8, 10 , Keith L. Ligon 1, 4, 8, 9, 10 , Shakti H. Ramkissoon 1, 4, 9, 10 1 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 5 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA 6 Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA 7 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 8 Broad Institute of MIT and Harvard, Cambridge, MA, USA 9 Department of Pathology, Boston Children’s Hospital, Boston, MA, USA 10 Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Shakti H. Ramkissoon, e-mail: sramkissoon@partners.org Keith L. Ligon, e-mail: keith_ligon@dfci.harvard.edu Keywords: spindle cell oncocytoma, pituitary, MAPK, HRAS, genomics Received: February 08, 2016     Accepted: April 16, 2016     Published: May 09, 2016 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.