Noninvasive diagnostic tools for cancer using circulating DNA
Cancer is a disease of the genome, characterized by and caused by variable patterns of genomic alterations. Cancer is difficult to treat because every cancer is different, and can further evolve over time and in response to treatment. Current methods for monitoring cancer dynamics are limited: protein markers and imaging estimate tumour burden, but can't assess genomic status. Biopsies give a snapshot of genomic changes, but can’t be used repeatedly. Better methods to study tumour evolution can promote research and greatly improve cancer care.
The Molecular and Computational Diagnostics group employs emerging molecular technologies to develop new diagnostic approaches. Our focus is on circulating tumour DNA (ctDNA) as a noninvasive modality to assess evolution of solid malignancies. This is DNA originating from cancer cells, carrying tumour-specific genomic alterations, that is present as short cell-free fragments in body fluids such as blood plasma. ctDNA can be collected noninvasively via blood samples and has the potential to be immensely informative.
The field of prenatal diagnostics is revolutionized by noninvasive tests that assay fetal DNA fragments in maternal plasma, spearheaded by work of Dennis Lo's group in Hong Kong. Parallel progress in cancer has been lagging, because genomic loci of interest are not well defined, and levels of tumour DNA in plasma are variable and generally lower: 2 ml of plasma may contain as many as 10,000 copies of DNA from healthy cells but only a few dozen copies of the tumour genome.
We use a combination of next-generation sequencing and digital PCR that allow sensitive measurement of rare alleles. We apply these to monitor mutation status and ctDNA levels in serial samples collected from patients during treatment and follow-up, in close collaboration with clinical and translational research groups. Changes in ctDNA levels may indicate disease progression and response to therapy. We've recently shown that ctDNA also allows noninvasive exploration of cancer genomics and clonal selection.
Taking this to the next level requires progress in several directions: improving our understanding of the relationship between tumour changes and ctDNA levels; developing sophisticated tools for ctDNA research and robust tools that can be used for routine analysis; and exploring the clinical implications of genomic changes and ctDNA dynamics.
Our lab is housed at the Cancer Research UK Cambridge Institute, part of the University of Cambridge and funded by Cancer Research UK. We are located on the campus of the Addenbrooke's Hospital, and are fortunate to have support of excellent core facilities, and close links to dedicated clinical researchers with whom we collaborate.