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. 2012 May 30;4(136):136ra68.
doi: 10.1126/scitranslmed.3003726.

Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA

Tim Forshew  1 , Muhammed Murtaza, Christine Parkinson, Davina Gale, Dana W Y Tsui, Fiona Kaper, Sarah-Jane Dawson, Anna M Piskorz, Mercedes Jimenez-Linan, David Bentley, James Hadfield, Andrew P May, Carlos Caldas, James D Brenton, Nitzan Rosenfeld
Affiliations

Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA

Tim Forshew et al. Sci Transl Med. .

Abstract

Plasma of cancer patients contains cell-free tumor DNA that carries information on tumor mutations and tumor burden. Individual mutations have been probed using allele-specific assays, but sequencing of entire genes to detect cancer mutations in circulating DNA has not been demonstrated. We developed a method for tagged-amplicon deep sequencing (TAm-Seq) and screened 5995 genomic bases for low-frequency mutations. Using this method, we identified cancer mutations present in circulating DNA at allele frequencies as low as 2%, with sensitivity and specificity of >97%. We identified mutations throughout the tumor suppressor gene TP53 in circulating DNA from 46 plasma samples of advanced ovarian cancer patients. We demonstrated use of TAm-Seq to noninvasively identify the origin of metastatic relapse in a patient with multiple primary tumors. In another case, we identified in plasma an EGFR mutation not found in an initial ovarian biopsy. We further used TAm-Seq to monitor tumor dynamics, and tracked 10 concomitant mutations in plasma of a metastatic breast cancer patient over 16 months. This low-cost, high-throughput method could facilitate analysis of circulating DNA as a noninvasive "liquid biopsy" for personalized cancer genomics.

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