Abstract
DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53 We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell-free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954-61. ©2016 AACR.
Highlights
Mutations acquired in a patient's tumor can be identified with deep sequencing with either targeted sequencing, where only the informative mutations for the clinical practice are screened, or whole-exome sequencing, to get a broader picture of the genetics of the tumor
We introduced the first method for identifying somatic mutations from whole-exome sequencing data that takes into account the possible presence of circulating tumor DNA (ctDNA)
We propose to use cmDetect as an additional step to traditional somatic mutations analysis pipelines when analyzing whole-exome sequencing of large sets of pairs of tumor/whole blood samples but it can be used as a standalone workflow for the identification of ctDNA mutations
Summary
Mutations acquired in a patient's tumor can be identified with deep sequencing with either targeted sequencing, where only the informative mutations for the clinical practice are screened, or whole-exome sequencing, to get a broader picture of the genetics of the tumor. For solid tumors, the germline DNA is often extracted from peripheral whole blood that may contain cell-free tumor DNA (cfDNA). DNA extracted from cancer patients' blood may contain various levels of tumor DNA called circulating tumor DNA (ctDNA). If the level of ctDNA in the blood is high enough, there is a possibility for some mutated DNA fragments to be detected by whole-exome sequencing of the DNA extracted from whole blood sample. This becomes a problem when these ctDNA mutations are detected in whole blood samples used as normal controls to distinguish somatic from germline events, preventing the accurate determination of somaticity. In a set of 829 breast carcinomas, 715 (86%)
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