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Circulating tumour-derived KRAS mutations in pancreatic cancer cases are predominantly carried by very short fragments of cell-free DNA

M. Zvereva, G. Roberti, G. Durand, C. Voegele, MD. Nguyen, TM. Delhomme, P. Chopard, E. Fabianova, Z. Adamcakova, I. Holcatova, L. Foretova, V. Janout, P. Brennan, M. Foll, GB. Byrnes, JD. McKay, G. Scelo, F. Le Calvez-Kelm

. 2020 ; 55 (-) : 102462. [pub] 20200403

Language English Country Netherlands

Document type Journal Article, Multicenter Study

Persistent link   https://www.medvik.cz/link/bmc21020568

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 (57 bp, 79 bp, 167 bp and 218 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 (167 bp and 218 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 218 bp assay relative to those detected with amplicons less than 80 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.

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$a Zvereva, Maria $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation
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$a 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 (57 bp, 79 bp, 167 bp and 218 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 (167 bp and 218 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 218 bp assay relative to those detected with amplicons less than 80 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.
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$a Roberti, Gabriel $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France; Santa Casa de Sao Paulo of medical Sciences, Sao Paulo, Brazil
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$a Durand, Geoffroy $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Voegele, Catherine $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Nguyen, Minh Dao $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Chopard, Priscilia $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Fabianova, Eleonora $u Regional Authority of Public Health, Banska Bystrica, and Faculty of Health, Catholic University, Ružomberok, Slovakia
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$a Adamcakova, Zora $u Regional Authority of Public Health, Banska Bystrica, and Faculty of Health, Catholic University, Ružomberok, Slovakia
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$a Holcatova, Ivana $u First Faculty of Medicine, Charles University of Prague, Institute of Hygiene and Epidemiology, Prague, Czechia
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$a Foretova, Lenka $u Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, Brno, Czechia
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$a Janout, Vladimir $u Faculty of Health Sciences, Palacky University, Olomouc, Czechia
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$a Brennan, Paul $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Foll, Matthieu $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Byrnes, Graham B $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a McKay, James D $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Scelo, Ghislaine $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France
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$a Le Calvez-Kelm, Florence $u International Agency for Research on Cancer (IARC), Genetic Cancer Susceptibility group, 150 Cours Albert Thomas, 69372 Lyon, France. Electronic address: lecalvezf@iarc.fr
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