Circulating tumour-derived KRAS mutations in pancreatic cancer cases are predominantly carried by very short fragments of cell-free DNA.
EBioMedicine
; 55: 102462, 2020 May.
Article
em En
| MEDLINE
| ID: mdl-32249202
ABSTRACT
BACKGROUND:
The DNA released into the bloodstream by malignant tumours· called circulating tumour DNA (ctDNA), is often a small fraction of total cell-free DNA shed predominantly by hematopoietic cells and is therefore challenging to detect. Understanding the biological properties of ctDNA is key to the investigation of its clinical relevance as a non-invasive marker for cancer detection and monitoring.METHODS:
We selected 40 plasma DNA samples of pancreatic cancer cases previously reported to carry a KRAS mutation at the 'hotspot' codon 12 and re-screened the cell-free DNA using a 4-size amplicons strategy (57â¯bp, 79â¯bp, 167â¯bp and 218â¯bp) combined with ultra-deep sequencing in order to investigate whether amplicon lengths could impact on the capacity of detection of ctDNA, which in turn could provide inference of ctDNA and non-malignant cell-free DNA size distribution.FINDINGS:
Higher KRAS amplicon size (167â¯bp and 218â¯bp) was associated with lower detectable cell-free DNA mutant allelic fractions (p < 0·0001), with up to 4·6-fold (95% CI 2·6-8·1) difference on average when comparing the 218bp- and the 57bp-amplicons. The proportion of cases with detectable KRAS mutations was also hampered with increased amplicon lengths, with only half of the cases having detectable ctDNA using the 218â¯bp assay relative to those detected with amplicons less than 80â¯bp.INTERPRETATION:
Tumour-derived mutations are carried by shorter cell-free DNA fragments than fragments of wild-type allele. Targeting short amplicons increases the sensitivity of cell-free DNA assays for pancreatic cancer and should be taken into account for optimized assay design and for evaluating their clinical performance.FUNDING:
IARC; MH CZ - DRO; MH SK; exchange program between IARC and Sao Paulo medical Sciences; French Cancer League.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Biomarcadores Tumorais
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Proteínas Proto-Oncogênicas p21(ras)
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Sequenciamento de Nucleotídeos em Larga Escala
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DNA Tumoral Circulante
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Observational_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2020
Tipo de documento:
Article