title: Computational optimisation of targeted DNA sequencing for cancer detection.
abstract: Despite recent progress thanks to next-generation sequencing technologies, personalised cancer medicine is still hampered by intra-tumour heterogeneity and drug resistance. As most patients with advanced metastatic disease face poor survival, there is need to improve early diagnosis. Analysing circulating tumour DNA (ctDNA) might represent a non-invasive method to detect mutations in patients, facilitating early detection. In this article, we define reduced gene panels from publicly available datasets as a first step to assess and optimise the potential of targeted ctDNA scans for early tumour detection. Dividing 4,467 samples into one discovery and two independent validation cohorts, we show that up to 76% of 10 cancer types harbour at least one mutation in a panel of only 25 genes, with high sensitivity across most tumour types. Our analyses demonstrate that targeting "hotspot" regions would introduce biases towards in-frame mutations and would compromise the reproducibility of tumour detection.
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Martinez
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D015331:Cohort Studies; D019295:Computational Biology; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D030541:Databases, Genetic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059645:Mutation Rate; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis* / Q000235:genetics; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm