Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.pdf (2.09 MB)
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Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.

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journal contribution
posted on 20.08.2019, 15:05 by NNM Myint, AM Verma, D Fernandez-Garcia, P Sarmah, PS Tarpey, SS Al-Aqbi, H Cai, R Trigg, K West, LM Howells, A Thomas, K Brown, DS Guttery, B Singh, HJ Pringle, U McDermott, JA Shaw, A Rufini
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.


Bowel Diseases Research Foundation Grant “Role of plasma nucleic acids for early detection and screening of colorectal cancers”, and by the Cancer Prevention Research Trust Grant “Analysis of tumor related circulating free DNA as cancer biomarker”, with assistance from Hope Against Cancer and Cancer Research UK in conjunction with the Department of Health as part of an Experimental Cancer Medicine Centre grant (C325/A15575). N.N.M.M. was supported by a Medical Research Council doctoral training grant, S.S.A. was funded by a studentship from the Iraqi Government.



Cell Death and Disease, 2018, 9 (9), pp. 894

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre


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Cell Death and Disease



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