Developing robust tests for cancer detection by cell-free DNA analysis in the UKCTOCS biobank

Primary supervisor: Nitzan Rosenfeld, Queen Mary University of London

Secondary supervisor: Usha Menon, UCL

Project

Aim: To identify cancer signal from small volumes of blood and other body fluids

The identification of cancer-specific alterations in cell-free DNA (cfDNA) derived from blood holds significant promise for early cancer detection [1]. Existing analysis methods often require the collection and processing of large volumes (>5ml) of plasma collected under specific conditions [2]. This leads to logistical and clinical testing complexities. Recent advances in cfDNA analysis, such as the extensive adoption of genome-wide multimodal assays and machine learning approaches, offer the potential to identify cancer signal from small volumes of blood and plasma. For a long time, plasma was the optimal source of material to be used in cfDNA profiling. Methods we are developing now allow us to generate good quality data from samples that have been collected using sub-optimal methods, by separating out tumour-derived cell-free DNA from high-molecular weight DNA from lysed blood cells [3].

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) Longitudinal Women’s Cohort (UKLWC, PI Prof Usha Menon) biorepository built in the course of UKCTOCS, contains serum samples stored as small aliquots (<500μl) from over 200,000 postmenopausal women from the general population who have been followed up for a median of 16.3 years [4]. The cohort includes women with incident cases of all cancer types (colorectal, pancreatic, melanoma, head & neck, breast, lung, ovarian) that occur in the older female population. The biorepository includes samples collected many years prior to incident cancer diagnosis including in 50,000 women, serial samples collected annually for 11 years (median 8 per women). The latter provide a unique opportunity to explore longitudinal biomarker profiling [5]. The proposed project will focus on optimizing and applying cfDNA analysis technologies for cancer detection in limited input DNA amounts of serum. We will utilize cutting-edge genomic methods and the unique UKCTOCS collection to develop sensitive assays for cfDNA analysis and evaluate their performance in the general population.

Candidate background

This project will suit candidates with background in DNA manipulation techniques (extraction, PCR, NGS library preparation), genomics/cancer genomics, NGS data analysis, and keen interest in early cancer detection. Understanding of cancer biology and challenges in handling limited amounts of DNA is an advantage.

Potential Research Placements

1. MRC clinical Trials Unit, UCL
2. TBC: Molecular biology methods and high-throughput sequencing
3. TBC: Bioinformatic methods and experience with NGS analysis

References

1. Micalizzi DS, Sequist LV, Haber DA. Deploying blood-based cancer screening. Science. 2024;383(6681):368-370.
2. Meddeb R, Pisareva E, Thierry AR. Guidelines for the Preanalytical Conditions for Analyzing Circulating Cell-Free DNA. Clin Chem. 2019;65(5):623-633.
3. Heider K, Wan JCM, Hall J, et al. Detection of ctDNA from dried blood spots after DNA size selection. Clin Chem. 2020;66(5):697-705.
4. Menon U, Gentry-Maharaj A, Burnell M, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021 Jun 5;397(10290):2182-2193.
5. Watson CJ, Poon GYP, MacGregor HAJ, et al. Evolutionary dynamics in the decades preceding acute myeloid leukaemia. bioRxiv. Published online July 10, 2024. doi:10.1101/2024.07.05.602251