title: The mutational landscape of adenoid cystic carcinoma.
abstract: Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Allen S
authors.initials: AS
authors.lastname: Ho
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.forename: David M
authors.initials: DM
authors.lastname: Roy
authors.forename: Luc G T
authors.initials: LG
authors.lastname: Morris
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.forename: Deepa
authors.initials: D
authors.lastname: Ramaswami
authors.forename: Logan A
authors.initials: LA
authors.lastname: Walsh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Eng
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.forename: Jianan
authors.initials: J
authors.lastname: Zhang
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Marija
authors.initials: M
authors.lastname: Drobnjak
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Leversha
authors.forename: Christine E
authors.initials: CE
authors.lastname: Rice
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: N Gopalakrishna
authors.initials: NG
authors.lastname: Iyer
authors.forename: C Rene
authors.initials: CR
authors.lastname: Leemans
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bloemena
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Gross
authors.forename: Yupu
authors.initials: Y
authors.lastname: Liang
authors.forename: Rileen
authors.initials: R
authors.lastname: Sinha
authors.forename: Luke
authors.initials: L
authors.lastname: Peng
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Gong
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.forename: Jatin P
authors.initials: JP
authors.lastname: Shah
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D000818:Animals; D019556:COS Cells; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D046888:Tissue Array Analysis