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A Comprehensive Genomic Mutation Profiling Analysis of Adenoid Cystic Carcinoma

The mutation signature of adenoid cystic carcinoma
26 Jun 2013
Pathology/Molecular biology;  Translational research;  Head and neck cancers

Adenoid cystic carcinoma is a slow-growing and often fatal malignancy that can occur at multiple organ site, but is most frequently found in the salivary glands. The primary treatment is surgical removal; however, the majority of patients develop metastatic disease. In a brief report published on 17 June 2013 in theJournal of Clinical Investigation, researchers led by Andrew Futreal of the Cancer Genome Project, Wellcome Trust Sanger Institute in Cambridge, United Kingdom, reported on a whole exome sequencing performed in 24 adenoid cystic carcinoma cases.

They uncovered the involvement of multiple cancer genes that are likely to be contributing to tumour development in the context of MYB activation. The data point to disruption of chromatin regulation as a major factor in adenoid cystic carcinoma development. Furthermore, the data implicate NOTCH signalling deregulation in a proportion of cases. Finally, the analysis has identified activating mutations of the receptor tyrosine kinase FGFR2 in a proportion of cases, thus suggesting a potential therapeutic point of attack on this rare but lethal cancer. In the accompanying commentary, Henry Frierson, Jr. of the University of Virginia emphasizes that identifying individual mutations will aid the development of personalized therapy for this disease.

While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else was known before this study about the molecular genetics of that frequently fatal cancer. The study researchers have undertaken exome sequencing in a series of 24 adenoid cystic carcinomas to further delineate the genetics of the disease. They identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and they identify the negative NOTCH signalling regulator, SPEN, as a new cancer gene in adenoid cystic carcinoma with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

The work in this study was supported by funding from the Adenoid Cystic Carcinoma Research Foundation and the Wellcome Trust (grant reference 077012/Z/05/Z), the USA NIH National Institute of Dental and Craniofacial Research (NIDCR), and the NIH Office of Rare Diseases Research (ORDR) (grant number U01DE019765). The authors S.M. Lippman and A.K. El-Naggar are supported by the NIH National Cancer Institute MD Anderson Cancer Center Head and Neck Specialized Program of Research Excellence (SPORE; P50 CA097007). P.J. Campbell is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P. Van Loo is a postdoctoral researcher of the Research Foundation — Flanders (FWO). A. Shlien is supported by the H.L. Holmes Award from the National Research Council Canada and an EMBO Fellowship. I. Varela is supported by a fellowship from The International Human Frontier Science Program Organization.

The lead author of the study Andrew Futreal is currently based in the Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Commenting on the study in the article entitled “Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming”, the editorialists pointed out that it is a comprehensive genomic mutation profiling analysis of this neoplasm and documents a common theme of alteration in chromatin regulatory genes. Also, mutations in SPEN (split ends, homolog of Drosophila), which encodes an RNA-binding coregulatory protein, suggest that other changes in transcriptional regulation may involve the NOTCH, FGFR, or other signalling pathways in which SPEN participates. Since there is a low prevalence of mutations in common oncogenes and tumour-suppressor genes, it is likely that alterations primarily in specific transcriptional regulatory genes, augmented by changes in chromatin structure, drive the neoplastic process in adenoid cystic carcinoma.


Stephens PJ, Davies HR, Mitani Y,et al.Whole exome sequencing of adenoid cystic carcinoma. J Clin Invest 2013 June 17. pii: 67201. doi: 10.1172/JCI67201. [Epub ahead of print].

Last update: 26 Jun 2013

The authors have declared that no conflict of interest exists.

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