| dc.contributor.advisor | Brockmöller, Jürgen Prof. Dr. | |
| dc.contributor.author | Hasheminasab, Sayedmohammad | |
| dc.date.accessioned | 2015-04-08T08:56:10Z | |
| dc.date.available | 2015-04-22T22:50:05Z | |
| dc.date.issued | 2015-04-08 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5FA3-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5009 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 610 | de |
| dc.title | Genomic variations in the EGFR pathway in relation to skin toxicity of EGFR inhibitors analyzed by deep sequencing | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Brockmöller, Jürgen Prof. Dr. | |
| dc.date.examination | 2015-04-22 | |
| dc.description.abstracteng | The development of targeted therapy has promised a new era in cancer therapy by improving response rates and fewer side effects of the therapeutics on normal cells. As the involvement of EGFR was noticed in several epithelial tumors, this receptor was identified as a target for cancer therapy already in 1983. However, EGFR inhibition seems to have its own class of side effects such as skin toxicity and diarrhea. These side effects remarkably occur only in a subgroup of patients with remarkable severity. Interestingly, the occurrence of skin toxicity was in almost all studies correlated with drug response and survival rate in treated patients. In this study we aimed to analyze the genetic variations in EGFR signaling pathway in patients receiving EGFR inhibition therapy using a deep sequencing method. If variants could be identified which significantly predicted skin toxicity, analysis for such variants would be used as biomarkers for individual drug dosing. In addition, the relationship between variants and phenotypes might contribute to our understanding of the skin rash with EGFR inhibition therapy.
Thirty genes reflecting the EGFR downstream pathway (PI3K/Akt and Ras/MAPK) and other genes involved such as IL8 and its receptors were targeted for resequencing. The whole EGFR gene along with 2000 bp of its promoter region was one of the targets. The total size of the re-sequenced EGFR gene was 196300 base pairs. For the remaining 29 other genes involved or presumed to be involved in rash physiopathology, the exons along with about 500 bp of the respective promoter regions were selected. We studied DNA samples from 126 patients who had been treated with EGFR inhibitors and in whom the adverse effects were characterized in detail. Before deep sequencing analysis was performed, three major steps: library preparation, target enrichment and template preparation were performed. Deep sequencing was executed using Ion Torrent Personal Genomics Machine TM (PGM). Variant calling was done by Torrent Variant Caller software. Statistical analysis was performed to survey the association of the identified variants with skin toxicity, diarrhea and overall survival.
Total 1437 single nucleotide variations were identified. These variations were present in more than 50% of subjects. From all variants found, 45% had less than 1% minor allele frequency and 65% of the variations had less than 5% minor allele frequency. Average minor allele frequency was 8.79% in this study. Three hundred and seventeen SNPs (22%) were not listed in the dbSNP 138. Three SNPs in intron 1 of EGFR were found to be strongly associated with the presence of rash. Intron 1 of EGFR was already shown earlier to be an important regulatory region for EGFR transcription. Furthermore, an ERK2 variation was found to be associated with high levels of skin rash. Pathway-based analysis of rare variations suggested the PI3K pathway to be involved in rash etiology. In addition to this finding, rs3730089 in PIK3R1 was found to have an association with skin rash and also a trend towards the better survival was found in patients having this variation. These two findings suggest the involvement of PIK3R1 in EGFR inhibitor induced skin toxicity.
A number of deleterious variations in EGFR pathway were announced for the first time including EGFR P560T, MTOR R2152H, and MAPK1 D336S which can be causal rare variations in cancer pathology. Previously reported biomarker candidate variations for EGFR inhibition related skin toxicity such as intron 1 CA repeat, -216G/T, and -190C/A were not studied and the rs2227983 single amino acid substitution was not significantly associated with skin toxicity. | de |
| dc.contributor.coReferee | Beißbarth, Tim Prof. Dr. | |
| dc.subject.eng | EGFR inhibitors | de |
| dc.subject.eng | Next generation sequencing | de |
| dc.subject.eng | skin toxicity | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5FA3-8-8 | |
| dc.affiliation.institute | Medizinische Fakultät | de |
| dc.subject.gokfull | Toxikologie | de |
| dc.subject.gokfull | Pharmakotherapie - Allgemein- und Gesamtdarstellungen | de |
| dc.subject.gokfull | Pharmakologie | de |
| dc.description.embargoed | 2015-04-22 | |
| dc.identifier.ppn | 821835521 | |