The mutational landscape of adenoid cystic carcinoma

Abstract

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary 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 revealed a low exonic somatic mutation rate (0.31 non-silent events/megabase) and wide mutational diversity. Interestingly, mutations selectively involved chromatin state regulators, such as SMARCA2, CREBBP, and KDM6A, suggesting aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to DNA damage and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying these aberrations as critical events. Lastly, we identified recurrent mutations in the FGF/IGF/PI3K pathway that may potentially offer new avenues for therapy (30%). Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

“…Another finding is that ACC tumors frequently produce high levels of the receptor tyrosine kinase c‐KIT (Figure 2) and variably overexpress other growth factor receptors, including fibroblast growth factor receptor 1 (FGFR1), epidermal growth factor receptor (EGFR), and/or human epidermal receptor‐2 (HER‐2) 2, 21, 22, 23. Although each of these receptors has the potential to generate oncogenic growth factor signals, mutational activation or overexpression because of gene amplification of the cognate genes is rare 24, 25. Thus, autocrine stimulation of these receptors is believed to lead to constitutive signaling.…”

“…ACC tumors exhibit nonrandom gains or losses of specific chromosome regions, including what may be an ACC‐specific deletion of chromosome 1p35–36. Other frequent deletions are located at 6q24, 12q, and 14q 23, 24, 25. However, the most intriguing alteration is a translocation between chromosomes 6q and 9p [(6;9)(q22–23;p23–24)].…”

“…Persson et al27, 28 were the first to report that this rearrangement juxtaposes the genes for the MYB and nuclear factor I/B (NFIB) transcription factors. This translocation seems to be specific for ACC, found in up to 86% of these tumors,24, 27, 28 and may be helpful in differentiating these tumors from other forms of carcinoma, such as pleomorphic adenoma 29, 30. One consequence of the rearrangement is the overexpression of a fusion transcript (perhaps related to absence of a 3′ negative regulatory element found in the normal MYB mRNA) as well as a largely intact MYB oncoprotein.…”

“…Interestingly, tumor suppressor genes and oncogenes that are frequently mutated in other cancers were uncommon. For example, the p53 tumor suppressor gene was mutated in only 3 of the 84 tumors in the 2 studies, whereas RAS or phosphotidylinositol‐3‐kinase (PI3K) growth factor signaling proteins were mutated in only 7 24, 25. Although a number of mutations were unique or only in a small fraction of the tumors, the altered genes could be grouped together by their potential to disrupt specific cellular functions or biochemical pathways.…”

“…Although a number of mutations were unique or only in a small fraction of the tumors, the altered genes could be grouped together by their potential to disrupt specific cellular functions or biochemical pathways. This included those that interact with the MYB transcription network, but also genes that influence chromatin remodeling, DNA damage/checkpoint responses, signaling pathways regulated by fibroblast growth factor (FGF)‐insulin‐like growth factor‐PI3K, protein kinase A pathway, or Notch 24, 25, 35, 36. Understanding the specific contribution of each mutation to tumorigenesis might lead to novel pathways for targeted therapy.…”