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Title: Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.
Authors: Myint, NNM
Verma, AM
Fernandez-Garcia, D
Sarmah, P
Tarpey, PS
Al-Aqbi, SS
Cai, H
Trigg, R
West, K
Howells, LM
Thomas, A
Brown, K
Guttery, DS
Singh, B
Pringle, HJ
McDermott, U
Shaw, JA
Rufini, A
First Published: 30-Aug-2018
Citation: Cell Death and Disease, 2018, 9 (9), pp. 894
Abstract: Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients' plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies.
DOI Link: 10.1038/s41419-018-0934-x
eISSN: 2041-4889
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Supplementary material is available from the publisher website at
Appears in Collections:Published Articles, Dept. of Genetics

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