Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Mohan, S; Heitzer, E; Ulz, P; Lafer, I; Lax, S; Auer, M; Pichler, M; Gerger, A; Eisner, F; Hoefler, G; Bauernhofer, T; Geigl, JB; Speicher, MR.
Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing.
PLoS Genet. 2014; 10(3):e1004271-e1004271 Doi: 10.1371/journal.pgen.1004271 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Führende Autor*innen der Med Uni Graz
Geigl Jochen Bernd
Mohan Sumitra
Speicher Michael
Co-Autor*innen der Med Uni Graz
Auer Martina
Bauernhofer Thomas
Eisner Florian
Gerger Armin
Heitzer Ellen
Höfler Gerald
Lafer Ingrid
Pichler Martin
Ulz Peter

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Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as KRAS, BRAF, PIK3CA, and EGFR. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of KRAS in four patients (40%), which occurred either as novel focal amplifications (n = 3) or as high level polysomy of 12p (n = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as MET (n = 2) and ERBB2 (n = 1). Overrepresentation of the EGFR gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of KRAS, BRAF, PIK3CA, and EGFR did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
Find related publications in this database (using NLM MeSH Indexing)
Aged -
Aged, 80 and over -
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal, Humanized - administration & dosage
Biomarkers, Tumor - blood
Cetuximab -
Colorectal Neoplasms - blood
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Drug Resistance, Neoplasm - genetics
Female -
Genome, Human -
High-Throughput Nucleotide Sequencing -
Humans -
Male -
Middle Aged -
Mutation -
Proto-Oncogene Proteins c-met - blood
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - immunology
Receptor, ErbB-2 - blood

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