Painting the Landscape of ACC Genomics
With each passing month, the picture of what drives the progression of adenoid cystic carcinoma becomes clearer and clearer. A team of researchers from the Wellcome Trust Sanger Institute and the M.D. Anderson Cancer Center has published an important article in the
Journal of Clinical Investigation entitled "Whole exome sequencing of adenoid cystic carcinoma". And researchers from the University of Virginia have authored an accompanying commentary on the article entitled "Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming".
The major findings of this sequencing study of 24 ACC cases are:
- The ACC genome is "quiet" with relatively few mutations compared to other tumor types.
- The MYB gene was activated in about 80% of cases, confirming its central role for most patients' disease.
- Chromatin remodeling factors were mutated in 50% of cases, implicating the machinery that packages DNA and controls expression.
- A novel cancer gene, SPEN, was identified and mutated in 7 of 66 cases (11%), all with solid histology. Solid histology indicates a poorer prognosis than the cribriform or tubular histologies of ACC.
- Mutations in NOTCH1 and NOTCH2 genes were found in 12% of cases. Additionally, SPEN is a purported regulator of the NOTCH pathway, pointing to its significance in a subset of patients.
- FGFR2 mutations in 6% of cases supports prior evidence on the importance of the FGF pathway in ACC.
The picture painted by this study is consistent with another journal article published last month with similar implications for ACC patients and their physicians. "Quiet" genomes with few alterations may be simpler to treat with targeted therapies, so tumor profiling may be instructive when considering systemic therapy. Unfortunately, the most common suspect in driving ACC, MYB, is not yet a molecular target that has been drugged effectively. However, genomic studies are identifying subsets of ACC patients with alterations in drugged targets that may lead to improved outcomes.
The study was funded primarily by ACCRF with additional support from the Wellcome Trust and the National Institutes of Health.
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