title: Mutant KRAS Status Is Associated with Increased KRAS Copy Number Imbalance: a Potential Mechanism of Molecular Heterogeneity.
abstract: Mutation rates determined by allele-specific PCR can be highly different in KRAS exon 2 mutant colorectal carcinoma (CRC) samples suggesting intratumoural heterogeneity. To address the effect of KRAS gene copy number on the relative mutant allele frequency the KRAS locus was individually quantified following FISH analysis in 36 cases. We observed, that mutant KRAS status was associated with an elevated KRAS locus number (2.36 ± 0.42 vs 2.63 ± 0.75; p = 0.037) reflecting an increased aneuploidy status but no true amplification of the locus. In parallel, KRAS locus copy numbers showed significant intercellular variability (1-16 copies/cell nucleus) within individual tumours also indicating to a dynamic intratumoural oscillation of the mutant allele copy number. In conclusion, aneusomy is a common feature of KRAS mutant CRC and KRAS copy number variations may have an impact on the relative mutant allele frequency detected by allele specific PCR/sequencing), potentially leading to subclonal diversity and influencing tumour behaviour.
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Ottó
authors.initials: O
authors.lastname: Dócs
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Hegyi
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Mokánszky
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Mónusné
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Lívia
authors.initials: L
authors.lastname: Beke
authors.affiliation: Department of Oncology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: András
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Bedekovics
authors.affiliation: Department of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary. gabor.mehes@med.unideb.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Méhes
mesh_terms: D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)
keywords: Amplification; CEP12; Colorectal cancer; Heterogeneity; KRAS