Whole exome sequencing of adenoid cystic carcinoma

Abstract

Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We 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 we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC 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.

Figure 1. Somatic mutations identified in known cancer genes, SPEN, and genes involved in chromatin biology.

The genes are listed on the left hand side and the adenoid cystic samples across the top. The darker shading at the bottom of the figure indicates genes involved in chromatin biology that have not previously been implicated in cancer.

Figure 2. SPEN and FGFR2 are cancer genes in ACC.

Representation of the somatic mutations identified in SPEN and FGFR2 relative to the protein coding sequence and major domains (A) indicating the position of somatic mutation identified in this study in SPEN. (B) Three somatic mutations identified in FGFR2 in this study are shown above the schematic; below are shown somatic mutations previously reported in endometrial and ovarian cancer and germline mutations in craniosynostosis syndromes.