Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity
| Autor: | Ajay Verma, Alessandro Rufini, Ultan McDermott, Howard Pringle, Saif Sattar Al-Aqbi, Daniel Fernandez-Garcia, Panchali B. Sarmah, Anne Thomas, Jacqui Shaw, Hong Cai, Lynne M. Howells, Karen Brown, Kevin West, Baljit Singh, Ricky M Trigg, David S. Guttery, Patrick S. Tarpey, Ni Ni Moe Myint |
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| Přispěvatelé: | Trigg, Ricky [0000-0001-9329-9344], Guttery, David S [0000-0003-0418-580X], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology Adenoma Male Proto-Oncogene Proteins B-raf Cancer Research medicine.medical_specialty Colorectal cancer Immunology Adenomatous Polyposis Coli Protein medicine.disease_cause Polymerase Chain Reaction Article Circulating Tumor DNA Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Internal medicine Cancer screening medicine Biomarkers Tumor Animals Humans Digital polymerase chain reaction lcsh:QH573-671 Early Detection of Cancer Aged Aged 80 and over Mice Knockout Genetic heterogeneity business.industry lcsh:Cytology Liquid Biopsy Cancer High-Throughput Nucleotide Sequencing Cell Biology Middle Aged medicine.disease 030104 developmental biology 030220 oncology & carcinogenesis Colonic Neoplasms Biomarker (medicine) DNA mismatch repair Female KRAS business |
| Zdroj: | Cell Death and Disease, Vol 9, Iss 9, Pp 1-16 (2018) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-018-0934-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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