title: KRAS mutations in blood circulating cell-free DNA: a pancreatic cancer case-control.
abstract: The utility of KRAS mutations in plasma circulating cell-free DNA (cfDNA) samples as non-invasive biomarkers for the detection of pancreatic cancer has never been evaluated in a large case-control series. We applied a KRAS amplicon-based deep sequencing strategy combined with analytical pipeline specifically designed for the detection of low-abundance mutations to screen plasma samples of 437 pancreatic cancer cases, 141 chronic pancreatitis subjects, and 394 healthy controls. We detected mutations in 21.1% (N=92) of cases, of whom 82 (89.1%) carried at least one mutation at hotspot codons 12, 13 or 61, with mutant allelic fractions from 0.08% to 79%. Advanced stages were associated with an increased proportion of detection, with KRAS cfDNA mutations detected in 10.3%, 17,5% and 33.3% of cases with local, regional and systemic stages, respectively. We also detected KRAS cfDNA mutations in 3.7% (N=14) of healthy controls and in 4.3% (N=6) of subjects with chronic pancreatitis, but at significantly lower allelic fractions than in cases. Combining cfDNA KRAS mutations and CA19-9 plasma levels on a limited set of case-control samples did not improve the overall performance of the biomarkers as compared to CA19-9 alone. Whether the limited sensitivity and specificity observed in our series of KRAS mutations in plasma cfDNA as biomarkers for pancreatic cancer detection are attributable to methodological limitations or to the biology of cfDNA should be further assessed in large case-control series.
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Foll
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Wozniak
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Delhomme
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Priscilia
authors.initials: P
authors.lastname: Chopard
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Maroulio
authors.initials: M
authors.lastname: Pertesi
authors.affiliation: Regional Authority of Public Health, Banska Bystrica, Slovakia.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fabianova
authors.affiliation: Regional Authority of Public Health, Banska Bystrica, Slovakia.
authors.forename: Zora
authors.initials: Z
authors.lastname: Adamcakova
authors.affiliation: Charles University of Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.affiliation: Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.affiliation: Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic.|Faculty of Medicine, University of Ostrava, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Vallee
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rinaldi
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Graham B
authors.initials: GB
authors.lastname: Byrnes
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Scelo
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D018395:CA-19-9 Antigen / Q000097:blood; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D000074141:Circulating Tumor DNA / Q000097:blood / Q000235:genetics*; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D010865:Pilot Projects; D011237:Predictive Value of Tests; D016283:Proto-Oncogene Proteins p21(ras) / Q000097:blood / Q000235:genetics*; D015203:Reproducibility of Results; D018154:Slovakia
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D000074141:Circulating Tumor DNA; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutations; cell-free DNA; pancreatic cancer detection; plasma