title: Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib.
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.
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Conroy
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Antonios
authors.initials: A
authors.lastname: Papanicolau-Sengos
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Sean T
authors.initials: ST
authors.lastname: Glenn
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Jacob
authors.initials: J
authors.lastname: Conroy
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Kiersten Marie
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: David E
authors.initials: DE
authors.lastname: Nowak
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Maochun
authors.initials: M
authors.lastname: Qin
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Angela R
authors.initials: AR
authors.lastname: Omilian
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Karen
authors.initials: K
authors.lastname: Head
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Blake
authors.initials: B
authors.lastname: Burgher
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Christopher
authors.initials: C
authors.lastname: Darlak
authors.affiliation: Department of Radiation Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: John
authors.initials: J
authors.lastname: Kane
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Mihai
authors.initials: M
authors.lastname: Merzianu
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Richard
authors.initials: R
authors.lastname: Cheney
authors.affiliation: Department of Surgery, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Andrew
authors.initials: A
authors.lastname: Fabiano
authors.affiliation: Department of Radiation Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Kilian
authors.initials: K
authors.lastname: Salerno
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Chetasi
authors.initials: C
authors.lastname: Talati
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Nikhil I
authors.initials: NI
authors.lastname: Khushalani
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;; Inova Dwight and Martha Schar Cancer Institute, Falls Church, Virginia 22042, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
keywords: pharyngeal neoplasm