Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes

We thank Polaris Pharmaceuticals and Bio-Cancer Treatment for providing drugs and reagents. This work was supported by the Cancer Prevention Research Trust, with assistance from the Wellcome Trust Institutional Strategic Support Fund [097828/z/11/B], and Cancer Research UK in conjunction with the Department of Health as part of an Experimental Cancer Medicine Centre grant [C325/A15575]. C.A. was funded by a PhD fellowship from the Cancer Prevention Research Trust, S.S.A. was funded by a studentship from the Iraqi Government. We are thankful to John Bomalaski and Sara Galavotti for their critical reading of the manuscript and insightful suggestions. Finally, we are profoundly indebted to Professor Andreas Gescher for his constant support during the execution of this project and the writing of this manuscript.Peer reviewedPublisher PD

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.

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