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Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000380. doi: 10.1101/mcs.a000380.

Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib.

Author information

1
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
2
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
3
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
4
Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
5
Department of Radiation Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
6
Department of Surgery, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
7
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
8
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;; Inova Dwight and Martha Schar Cancer Institute, Falls Church, Virginia 22042, USA.
9
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;

Abstract

Granular cell tumors are an uncommon soft tissue neoplasm. Malignant granular cell tumors comprise <2% of all granular cell tumors, are associated with aggressive behavior and poor clinical outcome, and are poorly understood in terms of tumor etiology and systematic treatment. Because of its rarity, the genetic basis of malignant granular cell tumor remains unknown. We performed whole-genome sequencing of one malignant granular cell tumor with metabolic response to pazopanib. This tumor exhibited a very low mutation rate and an overall stable genome with local complex rearrangements. The mutation signature was dominated by C>T transitions, particularly when immediately preceded by a 5' G. A loss-of-function mutation was detected in a newly recognized tumor suppressor candidate, BRD7. No mutations were found in known targets of pazopanib. However, we identified a receptor tyrosine kinase pathway mutation in GFRA2 that warrants further evaluation. To the best of our knowledge, this is only the second reported case of a malignant granular cell tumor exhibiting a response to pazopanib, and the first whole-genome sequencing of this uncommon tumor type. The findings provide insight into the genetic basis of malignant granular cell tumors and identify potential targets for further investigation.

KEYWORDS:

pharyngeal neoplasm

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