Identification of Oncogenic Mutations in Adenoid Cystic Carcinoma
Daniel Wetterskog, Daniel Nava Rodrigues, Karen Fritshie, Maryou B Lambros, Sami Shousha, Zoran Gatalica, Britta Weigelt, Anne Vincent-Salomon, Goran Stenman, Brian Rubin, Jorge S Reis-Filho. The Institute of Cancer Research, London, United Kingdom; Cleveland Clinic, Cleveland; Charing Cross Hospital, London, United Kingdom; Creighton University School of Medicine, Omaha, United Kingdom; Cancer Research UK London Research Institute, London, United Kingdom; Institut Curie, Paris, France; Sahlgrenska Cancer Center, Gothenburg, Sweden
Background: Adenoid cystic carcinomas (AdCCs) are malignant tumours that affect multiple anatomical sites, including the salivary gland, lung and breast. 30%-90% of these tumours harbour the MYB-NFIB fusion gene, caused by a t(6:9) translocation, which results in MYB overexpression. Salivary gland and breast AdCCs have distinct clinical behaviours; while salivary gland AdCCs are prone to distant relapses, patients with breast AdCCs have an excellent prognosis. The aim of this study was to investigate the presence of mutations in known oncogenes in AdCCs.
Design: Twelve MYB-NFIB-positive and one MYB-NFIB-negative breast AdCCs were microdissected to ensure >90% of tumour cell content, and DNA was extracted. The prevalence of hot-spot mutations in 19 known oncogenes was assessed using the Sequenom OncoCarta Panel v1.0, and validated with Sanger sequencing. Genes identified as mutated in any of the cases, and genes related to the same canonical pathways as those of the mutated genes, were sequenced in a separate cohort of 56 AdCCs (2 breast, 4 lung, 48 salivary gland, 1 pancreatic and 1 vaginal wall) using Sanger sequencing.
Results: Using Sequenom MassArray we identified BRAF mutations (i.e. V600E and G464E) in 2/13 breast AdCCs (15%), which were confirmed by Sanger sequencing. Both cases harbouring BRAF mutations were MYB-NFIB fusion-positive. No hotspot mutations in BRAF and other genes of the RAS-RAF pathway, namely NRAS, KRAS and HRAS, and also in KIT, a gene previously reported to be mutated in AdCCs, were identified in a separate cohort of 56 AdCCs by Sanger sequencing.
Conclusions: A subset of breast AdCCs, but not AdCCs from other anatomical sites, harbour activating BRAF mutations, albeit of low prevalence. These data provide evidence to suggest that the RAS-RAF pathway may be activated in tumours of indolent clinical outcome, such as breast AdCCs. Additional studies testing whether BRAF mutations constitute a 'driver' event in MYB-NFIB-positive AdCCs are warranted. Mutations in the genes assessed by Oncocarta v1.0 are unlikely to account for the differences in clinical behaviour between AdCCs of different anatomical sites. Finally, the lack of KIT mutations in our cohort suggests that KIT overexpression is unlikely to constitute a useful therapeutic target for AdCCs.
Category: Head & Neck
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 158, Tuesday Afternoon