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.

Highlights

  • Colorectal cancer (CRC) is the third most common malignancy, causing over 50,000 deaths per year in the United States[1]

  • Multi-regional targeted sequencing of adenomas Data from FFPE tissue suggested that the BRAF and KRAS mutations were present at low mutational fraction in most cases

  • We have used orthologous approaches to investigate the usefulness of cell-free DNA (cfDNA) testing in patients with benign polyps recruited to the Bowel Cancer Screening Programme (BCSP)

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Summary

Introduction

Colorectal cancer (CRC) is the third most common malignancy, causing over 50,000 deaths per year in the United States[1]. The probability of detecting ctDNA is low in early-stage CRC25 and different groups have reported dissimilar results with regard to the diagnostic value of total cfDNA levels or analysis of KRAS mutations in plasma of patients with adenomas[26,27,28,29]. Encouraging studies reported an increase in total cfDNA or even detected tumor-related mutations in patients with benign adenomas[26,28].

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