For the first time, researchers have gained insight into the molecular causes of acinic cell carcinoma, the third most common salivary gland cancer.
"Our research means that we can now diagnose acinic cell carcinomas in the salivary glands more easily and understand the fundamental biological processes behind tumor growth. In the long term, we hope that we will also be able to develop new ways of treating patients on the basis of this new research," commented Dr. Florian Haller, Professor in the Institute of Pathology at the Friedrich–Alexander University (FAU) and an author of the study, which was published in Nature Communications.
Acinic cell carcinoma has serous differentiation that closely resembles salivary glands' normal acini, clusters of cells that produce major components of saliva. To determine its causes, researchers at FAU Erlangen–Nuremburg, the German Cancer Research Centre in Heidelberg, and the Berlin Institute of Health performed comprehensive genomic, transcriptomic, and epigenomic profiling of acinic cell carcinomas and tissue of the parotid gland, a major salivary gland.
All of the acinic cell carcinomas that the investigators profiled contained recurrent rearrangements of genetic material between chromosomes 4 and 9 that translocated active enhancer regions from the SCPP gene cluster to the region above nuclear receptor subfamily 4 group A member 3 (NR4A3). In acinic cell carcinomas, NR4A3 was upregulated. The researchers found that active chromatin regions and gene expression signatures in acinic cell carcinomas correlated strongly with the NR4A3 transcription factor binding motif, the collection of NR4A3 transcription factor binding sites. In mouse salivary gland cells, NR4A3 overexpression increased expression of known NR4A3 target genes and stimulated cell proliferation.
The researchers conclude that NR4A3 upregulation is the result of "enhancer hijacking," in which malignant tumors are potentially caused by genetic rearrangements of DNA regulatory elements, and that NR4A3 plays an important oncogenic role in acinic cell carcinoma.
"The results of this study clearly indicate the correlation between the histomorphological features, or phenotype, of tumors and the genetic modification, or genotype, on which they are based," remarked Dr. Abbas Agaimy, Professor at FAU's Institute of Pathology and one of the study's authors.
Study author Matthias Bieg, MSc, a bioinformatician at the Berlin Institute of Health, emphasized the importance of the results: "Our interdisciplinary collaboration revealed that the shifting of epigenetic control elements can have a considerable impact on the development of tumors."
For More Information
Haller F, Bieg M, Will R, et al (2019). Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun, 10(1):368. DOI:10.1038/s41467-018-08069-x
Image credit: Nephron