Detecting epitranscriptomic signatures in circulating cell-free RNA for early cancer detection

Although recent advances in cancer research offer new ways to treat cancer, early detection still represents the best opportunity for curing cancer. Early stage treatment not only greatly improves patient survival but also costs considerably less. Therefore, a noninvasive, low cost and reliable cancer diagnostic assay could greatly benefit cancer patients and the public. In this regard, circulating nucleic acids hold tremendous potential to develop such a diagnostic assay. Human body fluids contain cell-free nucleic acids which originated from different cells of origin in the body including cancer cells in cancer individuals. Cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in circulation can be extracted for analysis and has potential use for diagnostics and prognostics of cancer. On the other hand, there are widespread chemical modifications in both DNA and RNA, which are terms epigenetic modifications and epitranscriptomic modifications, respectively. The presence of tumours can alter the epigenetic and epitranscriptomic landscape at both tumour sites including cancer cells and microenvironment as well as distant cells such as cells of the immune system. While epigenetic modifications can be readily detected in cfDNA and extensively used for cancer detection, epitranscriptomic modifications in cfRNA have not been explored due to technological difficulties.

Our research aims to decode epigenetic and epitranscriptomic modifications of our genome and transcriptome to learn about the basis of human health and disease, and to facilitate translation of this information into diagnostic and therapeutic opportunities that ultimately benefit patients. With our unique expertise in chemical biology and genome technology, we have developed cutting-edge technologies in epigenetics and epitranscriptomics. Previously, we developed a DNA epigenetic modification sequencing method, and demonstrated its application in cfDNA sequencing for early cancer detection (Nat. Biotechnol. 2019, 37, 424, Sci. Adv. 2021, 7, eabh0534).

Recently, we developed a novel sequencing method, called BACS, for the most abundant RNA epitranscriptomic modification pseudouridine (Nat. Methods 2024, 21, 2024). Pseudouridine is the most common post-transcriptional RNA modification linked to various diseases, including cancer. Our previous work has shown that the BACS method significantly outperforms older techniques in detecting pseudouridine, demonstrating its ability to identify this modification accurately and sensitively at a single-base resolution.

We plan to explore the potential clinical application of pseudouridine in cfRNA for early cancer detection using BACS. cfRNA encompass a diverse array of extracellular transcripts, including both coding and non-coding RNAs (ncRNAs) in the bloodstream. These cfRNAs originate from processes such as cell death and active secretion via extracellular vesicles, positioning them as promising biomarkers for liquid biopsy. Current detection methods for cfRNA in plasma largely focus on coding RNAs, or messenger RNAs (mRNAs), which represent only a small fraction (~2%) of the cfRNA repertoire, while the vast amount of ncRNAs are overlooked. By focusing on the highly abundant pseudouridine in ncRNAs in cfRNA, this research has the potential to transform cancer detection by providing a non-invasive, accurate, and cost-effective method for identifying new cancer biomarkers in patient blood samples.

Students with a Chemistry or Biochemistry or a related science background are welcome to apply. Training opportunities include a wide range of basic and advanced chemical biology, biochemistry, and molecular biology techniques; knowledge in nucleic acid modifications/epigenetics/epitranscriptomics and clinical diagnostics; cutting-edge technologies, such as next-generation sequencing, cell-free RNA sequencing (liquid biopsy), bioinformatics and data analysis skills, including the use of machine learning and AI.

Funding Notes

Ludwig studentships provide 4 years funding for a tax-free stipend, currently £21,000 pa and university fees at home and international rates.

Only applications made by the University of Oxford application system for a DPhil in Clinical Medicine will be considered. You may apply for a maximum of two Ludwig projects. Under proposed field and title of research project please enter the project titles in the order of preference. You do not need to provide a research proposal but must include a personal statement.

Please ensure referees are willing to write and submit your reference by the deadline.

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 Applications

https://www.ox.ac.uk/admissions/graduate/courses/dphil-clinical-medicine