Posted: October 20, 2015

Researchers Use TCGA Data for First Pan-Cancer Analyses of RNA-Editing

Amy E Blum, M.A.

A decade after TCGA began collecting tissue samples for characterization, the richness of the TCGA dataset continues to enable the most current and cutting edge cancer genomics research, often facilitating research that goes beyond the scope of the original goals of the project. In three independent studies published simultaneously on October 1 in Cell Reports and Cancer Cell, scientists used TCGA data to perform the first pan-cancer analyses of RNA editing, a recently recognized form of genetic regulation.

Cancer is driven by alterations in the genome, most commonly through mutations in DNA that deregulate normal cellular functions and push cell growth into overdrive. However, DNA mutations are not the only way to alter genetic sequence information. Over the last five years, next generation sequencing has revealed that RNA editing, a process through which changes are made to the nucleotide sequences of RNAs, is a widespread regulatory phenomenon, with more than a million sites of editing detected so far in humans.1 Yet our understanding of RNA editing and how it influences human diseases is still in its infancy, as research on RNA editing has been limited to normal tissue or isolated cancer types. The first genome-wide analyses of RNA editing sites using TCGA data have now revealed that RNA editing levels are significantly altered across cancer types, and some sites may even act as cancer drivers.
RNA Editing is Significantly Altered in Cancer

 Three separate groups of investigators utilized TCGA data to carry out genome-wide analyses of RNA editing sites. The studies focused on the most common form of RNA editing in humans, A-to-I editing, in which the nucleotide adenosine is changed to inosine. By comparing A-to-I editing sites in TCGA tumor and matched normal samples, researchers observed elevated levels of A-to-I RNA editing in most cancer types, indicating that RNA editing contributes to the diversity of the cancer transcriptome. Kidney cancer was a notable exception to the trend. Though RNA-editing was significantly altered, kidney cancer tumors contained fewer editing sites compared to matched normal tissue.

All three studies agreed on the source of the elevated RNA editing: increased levels of ADAR1, an enzyme that catalyzes A-to-I editing. The expression of the ADAR gene in TCGA RNA-seq data correlated strongly with the amount of RNA editing found in tumors (Han et al., 2015; Paz et al., 2015). On the other hand, expression of ADAR2 and ADAR3, alternate isoforms of the ADAR enzyme, were not associated with overall editing levels. Fumagalli and colleagues validated the role of ADAR1 by inducing its expression in breast cell lines. Inducing ADAR1 increased the number of RNA editing sites and the frequency of A-to-I edits at those sites (Fumagalli et al., 2015).

The Role of A-to-I Edits in Cancer

RNA edits are similar to DNA mutations in that most occurrences are simply passengers, but sites that modulate RNA or protein function may be clinically significant. In some cancers, including head and neck, liver, and breast, higher levels of editing corresponded with less favorable patient outcomes (Paz et al. 2015). In normal and cancer cell lines, altering the levels of editing influenced cell survival, proliferation and apoptosis, indicating that A-to-I editing may contribute to the uncontrolled growth observed in cancer (Fumagalli et al., 2015; Han et al., 2015).

RNA editing may also have a direct impact on the effectiveness of certain treatments, potentially explaining why some patients respond to a targeted therapy when they do not have the corresponding DNA mutation. Han and colleagues identified several RNA editing sites across multiple cancers that correlated with clinical parameters such as tumor subtype, tumor stage, or clinical outcome. Some of these clinically relevant RNA edits had been studied previously in the context of specific cancer types, while others had not yet been characterized. The researchers tested clinically relevant RNA editing sites in a drug sensitivity screen and found that cancer cells with certain edited RNAs responded differently to targeted therapies, suggesting that RNA editing may mediate patients’ responses to treatment (Han et al,. 2015).

A Role for TCGA in the Future of Cancer Genomics

Through the use of TCGA data, these preliminary results suggest that RNA edits have a significant role as potential drivers and contributors to cancer progression across many cancer types, and that they could be targeted by new therapies or used to predict patient outcomes.

TCGA’s vision of a comprehensive map of many cancer types to serve as a foundation for future cancer research is coming to fruition, as the data continue to provide a valuable resource for new genomic investigations.

Fumagalli, D., Gacquer, D., Rothe, F., Lefort, A., Libert, F., Brown, D. Kheddoumi, N., Shlien, A., Konopka, T., Salgado, R. et al. (2015) Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome. Cell Reports. 13:277-289

Han, L., Diao, L., Yu, S., Xu, X., Li, J., Zhang, R., Yang, Y., M.J., H., A, W., Eterovic, K., et al. (2015) The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. Cancer Cell. 28:515-528.

Paz-Yaacov, N., Bazak, L., Buchumenski, I., Porath, H.T., Danan-Gotthold, M., Knisbacher, B.A., Eisenberg, E., and Levanon, E.Y (2015) Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors. Cell Reports. 13:267-276

Selected References

1 Bazak, L., Haviv, A., Barak, M., Jacob-Hirsch, J., Deng, P., Zhang, R., Isaacs, F.J., Rechavi, G., Billy Li, J. Eisenberg, E., et al. (2014) A-to-I RNA editing occurs at over a hundred million genomic sites, located in the majority of human genes. Genome Research. 24:365-376.