Oncotarget

Research Papers:

MAPK activation and HRAS mutation identified in pituitary spindle cell oncocytoma

Michael B. Miller _, Wenya Linda Bi, Lori A. Ramkissoon, Yun Jee Kang, Malak Abedalthagafi, David S. Knoff, Pankaj K. Agarwalla, Patrick Y. Wen, David A. Reardon, Brian M. Alexander, Edward R. Laws Jr., Ian F. Dunn, Rameen Beroukhim, Keith L. Ligon and Shakti H. Ramkissoon

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Oncotarget. 2016; 7:37054-37063. https://doi.org/10.18632/oncotarget.9244

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Abstract

Michael B. Miller1,*, Wenya Linda Bi2,3,10,*, Lori A. Ramkissoon4, Yun Jee Kang4, Malak Abedalthagafi1, David S. Knoff4, Pankaj K. Agarwalla3,5, Patrick Y. Wen4,10, David A. Reardon4,10, Brian M. Alexander6,7,10, Edward R. Laws Jr.2,10, Ian F. Dunn2,10, Rameen Beroukhim3,4,8,10, Keith L. Ligon1,4,8,9,10, Shakti H. Ramkissoon1,4,9,10

1Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

2Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA

3Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

5Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

6Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA

7Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

8Broad Institute of MIT and Harvard, Cambridge, MA, USA

9Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

10Harvard Medical School, Boston, MA, USA

*These authors have contributed equally to this work

Correspondence to:

Shakti H. Ramkissoon, e-mail: [email protected]

Keith L. Ligon, e-mail: [email protected]

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.


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