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Identifier

000382573

Title

Ανίχνευση μεταλλάξεων του EGFR και KRAS σε ασθενείς με μη-μικροκυτταρικό καρκίνο του πνεύμονα και διερεύνηση της αξίας τους ως προβλεπτικών παραγόντων ανταπόκρισης στη θεραπεία

Alternative Title

Detection of EGFR and KRAS mutations in patients with non-small cell lung cancer and investigate their value as predictive markers of response to treatment

Author

Καλυκάκη, Αριστέα Ν

Thesis advisor

Γεωργούλιας, Βασίλειος

Reviewer

Μαυρουδής, Δημήτριος
Θεοδωρόπουλος, Παναγιώτης
Σταθόπουλος, Ευστάθιος
Αγγελάκη, Σοφία
Κουτσόπουλος, Αναστάσιος
Κωτσάκης, Αθανάσιος

Abstract

The purpose of this study was to investigate whether the EGFR and KRAS mutation status are predictive factors for Greeks patients with NSCLC. Initially, we calculated the rate and the pattern of EGFR and KRAS mutations in 639 patients with NSCLC and then we correlated the mutations status with clinicopathological characteristics, the response to 1st line chemotherapy and patients’ overall survival. We also investigated the association of EGFR mutations with the EGFR gene amplification. Finally, in a group of 25 patients the mutation status of these genes in the primary tumors and the corresponding metastasis was evaluated. The genetic analysis performed in FFPE tissue samples of primary tumor or metastasis. DNA was extracted using universal techniques. For mutation analysis exons 18, 19, 20 and 21 of the EGFR and exon 2 of KRAS genes were sequentially amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. Finally, EGFR amplification was determined by quantitative real time PCR. Analysis of EGFR mutations was successful performed in 634 patients and mutations were detected in 100 (15.8%) of them. Activating mutations were detected in 8.4%. The most common mutations were deletions of 4-5 codons in exon 19 (del 19, 71.7%, 38/53) and the missense mutation at position 858 (L858R) in exon 21 (22.6%, 12/53). Also in 47 (7.4%) patients other mutations were detected in four exons of EGFR, which have been reported previously or are new. We found that the incidence of EGFR mutations was statistically significant in women with no smoking history and with adenocarcinoma histology. The mutation analysis of the KRAS gene was successfully performed on 399 patients and mutations detected in 20.8% of them (83/399). Especially, 92.8% of the mutations were found at codon 12 and 7.2% at codon 13. KRAS mutations were significantly associated with smoking history with higher incidence in smokers than nonsmokers. There was also a significant association between KRAS mutations and adenocarcinoma histology. The predictive value of EGFR and KRAS mutations was examined in a subgroup of patients (n=162) with NSCLC who received chemotherapy as 1st line therapy. Patients with classical EGFR mutations had a higher probability of response (55.6%) to vii front-line chemotherapy as compared to those with wild type EGFR (21.8%) (p = 0.023). Multivariate analysis revealed the 'classical' activating EGFR mutations as an independent predictive factor for response to 1st line chemotherapy. There was no significant correlation between the EGFR or KRAS mutation status and the time to tumor progression. The presence of activating EGFR but not of KRAS mutations was associated with a significantly higher overall survival compared to patients without mutations treated with platinum-based front-line chemotherapy. Epidermal growth factor receptor and KRAS mutation status was different between primary tumors and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. This discrepancy was not statistically significant with the McNemar’s test. EGFR amplification was found in 7.2% (6/83) of primary tumors. Among the patients with EGFR gene amplification none carried KRAS mutations while 2 had EGFR exon 19 deletion.

Language

Greek

Subject

EGFR gene

KRAS gene

Mutations

NON-small cell lung cancer

Predictive marker

Γονίδιο του EGFR

Γονίδιο του KRAS

Μεταλλάξεις

Μη-μικροκυτταρικός καρκίνος του πνεύμονα