Skip to main content
Erschienen in: Pathology & Oncology Research 2/2017

15.10.2016 | Original Article

Mutant KRAS Status Is Associated with Increased KRAS Copy Number Imbalance: a Potential Mechanism of Molecular Heterogeneity

verfasst von: Ottó Dócs, Katalin Hegyi, Attila Mokánszky, Anikó Mónusné, Lívia Beke, Csilla András, Judit Bedekovics, Gábor Méhes

Erschienen in: Pathology & Oncology Research | Ausgabe 2/2017

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A (2009) Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205(12):858–862CrossRefPubMed Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A (2009) Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205(12):858–862CrossRefPubMed
2.
Zurück zum Zitat Lièvre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995CrossRefPubMed Lièvre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995CrossRefPubMed
3.
Zurück zum Zitat van Krieken JH, Jung A, Kirchner T et al (2008) KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 453(5):417–431CrossRefPubMed van Krieken JH, Jung A, Kirchner T et al (2008) KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 453(5):417–431CrossRefPubMed
4.
Zurück zum Zitat Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634CrossRefPubMed Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634CrossRefPubMed
5.
Zurück zum Zitat Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765CrossRefPubMed Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765CrossRefPubMed
6.
Zurück zum Zitat Yu S, Xiao X, Lu J, Qian X, Liu B, Feng J (2013) Colorectal Cancer Patients with Low Abundance of KRAS Mutation May Benefit from EGFR Antibody Therapy. PLoS One 8(7) Yu S, Xiao X, Lu J, Qian X, Liu B, Feng J (2013) Colorectal Cancer Patients with Low Abundance of KRAS Mutation May Benefit from EGFR Antibody Therapy. PLoS One 8(7)
7.
Zurück zum Zitat Dócs O, Fazakas F, Horváth NL et al (2015) Changes of KRAS exon 2 codon 12/13 mutation status in recurrent colorectal cancer. Pathol Oncol Res 21(2):399–404CrossRefPubMed Dócs O, Fazakas F, Horváth NL et al (2015) Changes of KRAS exon 2 codon 12/13 mutation status in recurrent colorectal cancer. Pathol Oncol Res 21(2):399–404CrossRefPubMed
8.
Zurück zum Zitat Bakhoum SF, Compton DA (2012) Chromosomal instability and cancer: a complex relationship with therapeutic potential. J Clin Invest 122(4):1138–1143CrossRefPubMedPubMedCentral Bakhoum SF, Compton DA (2012) Chromosomal instability and cancer: a complex relationship with therapeutic potential. J Clin Invest 122(4):1138–1143CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Orum H, Nielsen PE, Egholm M, Berg RH, Buchardt O, Stanley C (1993) Single base pair mutation analysis by BNA directed PCR clamping. Nucleic Acids Res 21(23):5332–5336CrossRefPubMedPubMedCentral Orum H, Nielsen PE, Egholm M, Berg RH, Buchardt O, Stanley C (1993) Single base pair mutation analysis by BNA directed PCR clamping. Nucleic Acids Res 21(23):5332–5336CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Cappuzzo F, Hirsch FR, Rossi E et al (2005) Epidermal growth factor receptor Gene and Protein and Gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst 97(9):643–655CrossRefPubMed Cappuzzo F, Hirsch FR, Rossi E et al (2005) Epidermal growth factor receptor Gene and Protein and Gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst 97(9):643–655CrossRefPubMed
11.
Zurück zum Zitat Fehrmann RS, Karjalainen JM, Krajewska M et al (2015) Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat Genet 47(2):115–125CrossRefPubMed Fehrmann RS, Karjalainen JM, Krajewska M et al (2015) Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat Genet 47(2):115–125CrossRefPubMed
12.
Zurück zum Zitat Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6(5):279–286CrossRefPubMed Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6(5):279–286CrossRefPubMed
13.
Zurück zum Zitat Seth R, Crook S, Ibrahem S, Fadhil W, Jackson D, Ilyas M (2009) Concomitant mutations and splice variants in KRAS and BRAF demonstrate complex perturbation of the ras/Raf signalling pathway in advanced colorectal cancer. Gut 58(9):1234–1241CrossRefPubMed Seth R, Crook S, Ibrahem S, Fadhil W, Jackson D, Ilyas M (2009) Concomitant mutations and splice variants in KRAS and BRAF demonstrate complex perturbation of the ras/Raf signalling pathway in advanced colorectal cancer. Gut 58(9):1234–1241CrossRefPubMed
14.
Zurück zum Zitat Valtorta E, Misale S, Sartore-Bianchi A et al (2013) KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy. Int J Cancer 133(5):1259–1265CrossRefPubMed Valtorta E, Misale S, Sartore-Bianchi A et al (2013) KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy. Int J Cancer 133(5):1259–1265CrossRefPubMed
16.
Zurück zum Zitat Hegyi K, Méhes G (2012) Mitotic failures in cancer: aurora B kinase and its potential role in the development of aneuploidy. Pathol Oncol Res. 18(4):761–769CrossRefPubMed Hegyi K, Méhes G (2012) Mitotic failures in cancer: aurora B kinase and its potential role in the development of aneuploidy. Pathol Oncol Res. 18(4):761–769CrossRefPubMed
17.
Zurück zum Zitat Soh J, Okumura N, Lockwood WW et al Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumour cells. PLoS One s4(10):e7464 Soh J, Okumura N, Lockwood WW et al Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumour cells. PLoS One s4(10):e7464
Metadaten
Titel
Mutant KRAS Status Is Associated with Increased KRAS Copy Number Imbalance: a Potential Mechanism of Molecular Heterogeneity
verfasst von
Ottó Dócs
Katalin Hegyi
Attila Mokánszky
Anikó Mónusné
Lívia Beke
Csilla András
Judit Bedekovics
Gábor Méhes
Publikationsdatum
15.10.2016
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 2/2017
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0126-x

Weitere Artikel der Ausgabe 2/2017

Pathology & Oncology Research 2/2017 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.