Profiling lung adenocarcinoma by liquid biopsy: can one size fit all?

Harry W. Clifford, Amy P. Cassidy, Courtney Vaughn, Evaline S. Tsai, Bianka Seres, Nirmesh Patel, Hannah L. O’Neill, Emil Hewage, John W. Cassidy

Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing. Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci. We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma. With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner.