• Dr. Christopher Smith

Urological Malignancies Programme award moves biomarker research forward

My name is Christopher Smith and I am a research associate based in Nitzan Rosenfeld’s lab at the CRUK Cambridge Institute. A year ago, I was awarded funding through the Urological Malignancies pump priming grant. Using these funds, I have been able to explore the clinical utility of liquid biopsy in patients with urological malignancies, building upon the lab’s previous findings in renal (Smith et al, 2020) and bladder (Patel et al, 2017) cancers.

Recent years have seen an explosion in the number of studies assessing cell-free tumour derived DNA (ctDNA) as an alternative to traditional invasive tumour sampling (Bettegowda et al, 2014; Wan et al, 2020; Smith et al, 2020; Patel et al, 2017, Mouliere et al, 2018). The field is now in an exciting transitionary phase with ctDNA analysis beginning to be applied clinically. Despite this progress, there are still several challenges faced in the application of this biomarker. Foremost amongst these are the small quantities of ctDNA in the blood stream; even in patients with advanced cancers, ctDNA makes up (on average) only ~10% of the total cell-free DNA population, which is itself limited. This makes it a challenge to apply ctDNA based assays as, very often, their target simply isn’t present (potentially leading to false negative findings). One way to get around this is to increase the number of targets!

ctDNA studies have traditionally focused on DNA originating from the nuclear genome, with little consideration of the other fragments that make up the overall population of cfDNA in a given tube of blood or urine. However, the field is starting to explore fragments that originate from other sources e.g. cells of the microbiome, extracellular vesicles, and, pertinent to this project, mitochondria. Here, I aim to determine whether mitochondrial cfDNA contains information about a patient’s tumour that mirrors or complements that carried by nuclear cfDNA.

There are several reasons why analysis of mtDNA could prove advantageous. Chief amongst these is the fact that there are several copies of the mitochondrial genome per mitochondria, as well as several mitochondria per cell. Thus, there is a large pool of genomic material that can contribute to the overall population of cfDNA. The same could apply to tumour cells. Indeed, our group previously demonstrated that tumour-derived mtDNA is more frequently detected in plasma than nuclear ctDNA (Mair et al, 2018). Furthermore, much like the nuclear genome, somatic mutations and copy number events of the ~16,500bp mitochondrial genome can occur.

Combined, these factors highlight how mitochondrial ctDNA could add considerably to number of targets available for ctDNA-based assays.

Over the course of the past year I have carried out a preliminary assessment of the quantities of mitochondria derived cfDNA in renal and bladder cancers (as well as other cancer types) – early indications suggest that there are differences between cancer types and these differences might be used for classification of samples. Furthermore, I have carried out mutation analysis of matched tumour tissue, plasma and urine from patients with renal cancer, and identified somatic mutations of the mitochondrial genome.

Whilst these findings are promising (and exciting!), more data are needed to validate my initial observations. Thus, the next year will be spent in the lab applying pre-existing (and new!) assays to yet more samples, and at the desk carrying out computational analysis of sequencing data.

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The Cambridge Urological Malignancies Programme is part of the CRUK Cambridge Centre, funded by Cancer Research UK Major Centre Award C9685/A25117, and supported by the NIHR Cambridge BRC.