Journal Article

The mutational landscape of adenoid cystic carcinoma

Morris, Luc G T, Gong, Yongxing, Schultz, Nikolaus, Ferris, Robert L, Sander, Chris, Ganly, Ian, Dolgalev, Igor, Zhang, Jianan, Walsh, Logan A, Rice, Christine E, Liang, Yupu, Eng, Stephanie, Seethala, Raja R, Drobnjak, Marija, Ho, Allen S, Peng, Luke, Heguy, Adriana, Huberman, Kety, Roy, David M, Turcan, Sevin, Sinha, Rileen, Raphael, Benjamin J, Gross, Benjamin E, Leemans, C Rene, Iyer, N Gopalakrishna, Katabi, Nora, Lee, William, Singh, Bhuvanesh, Viale, Agnes, Chiosea, Simion, Ramaswami, Deepa, Shah, Jatin P, Kannan, Kasthuri, Leversha, Margaret A, Kim, Seungwon, Huse, Jason T, Bloemena, Elisabeth, Chan, Timothy A

2013

Overview

Timothy Chan and colleagues report exome and genome sequencing of 60 adenoid cystic carcinoma (ACC) tumor-normal pairs. They identify multiple pathways recurrently disrupted in ACC and provide evidence that KDM6A and PIK3CA are functionally relevant candidate ACC driver genes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114/2785 / 631/208/212 / 692/699/67/1536 / Adenolymphoma / Agriculture / Analysis / Animal Genetics and Genomics / Animals / Biomedicine / Cancer / Cancer Research / Cancer therapies / Carcinoma, Adenoid Cystic - genetics / Carcinoma, Adenoid Cystic - metabolism / Case-Control Studies / Cell Transformation, Neoplastic - genetics / Cells, Cultured / Chlorocebus aethiops / COS Cells / Deoxyribonucleic acid / DNA / DNA damage / DNA Mutational Analysis / Gene Expression Profiling / Gene Function / Genetic aspects / Genetic Association Studies / Genomes / Genomics / Hematology / Histology / Human Genetics / Humans / Kinases / letter / Models, Biological / Mutation / Mutation - physiology / Proteins / Risk factors / Salivary Gland Neoplasms - genetics / Salivary Gland Neoplasms - metabolism / Signal Transduction - genetics / State regulations / Tissue Array Analysis