%0 Journal Article
%T Detection of low prevalence somatic mutations in solid tumors with ultra-deep targeted sequencing
%A Olivier Harismendy
%A Richard B Schwab
%A Lei Bao
%A Jeff Olson
%A Sophie Rozenzhak
%A Steve K Kotsopoulos
%A Stephanie Pond
%A Brian Crain
%A Mark S Chee
%A Karen Messer
%A Darren R Link
%A Kelly A Frazer
%J Genome Biology
%D 2011
%I BioMed Central
%R 10.1186/gb-2011-12-12-r124
%X The number of somatic tumor mutations with potential utility for predicting treatment response is rapidly growing due to increasing numbers of targeted therapies. Clinical validation of these potential biomarkers has been slowed by both issues with tumor samples and the current paradigm underlying cancer clinical trials. Tumor DNA samples can be heterogeneous due to invasion into stroma, infiltration by immune cells, and clonal evolution. Efforts to overcome this heterogeneity have, to date, required highly focused testing of no more than a few dozen known mutations, significantly limiting progress. Additionally, cancer drug development has traditionally focused on a tissue of origin model, where efficacy studies are focused on cancers arising from one tissue type. As molecular subtyping has emerged, molecularly defined trials have been restricted to common DNA alterations (for example, Imatinib and KIT gene mutations in gastro-intestinal stromal tumors) [1] or uncommon alterations in very common tumors (for example, Erlotinib and EGFR-L858R in non-small cell lung cancer) [2]. The identification of an increasing number of somatic tumor mutations common across cancers arising from different tissues has begun to encourage molecularly defined clinical trials in which subjects with cancers from a number of differing sites of origin are eligible. To accelerate this paradigm shift, an assay capable of broad mutation testing in heterogeneous tumor samples is needed.Somatic mutations can affect key domains of cancer genes. These mutations, associated with cancer progression and resistance to therapy, exist in restricted regions of the genome, termed mutational hotspots. Additionally, actionable mutations, in which an approved or investigational agent is available to target a pathway activated by the mutation, exist in an even more restricted set of these genomic regions. While most available clinical assays interrogate one or only a few commonly mutated loci in cancers, two
%U http://genomebiology.com/2011/12/12/R124