|
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.
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Language |
Greek |
Subject |
EGFR gene |
|
KRAS gene |
|
Mutations |
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NON-small cell lung cancer |
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Predictive marker |
|
Γονίδιο του EGFR |
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Γονίδιο του KRAS |
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Μεταλλάξεις |
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Μη-μικροκυτταρικός καρκίνος του πνεύμονα |
|
Προβλεπτικός δείκτης |
Issue date |
2014-01-22 |
Collection
|
School/Department--School of Medicine--Department of Medicine--Doctoral theses
|
|
Type of Work--Doctoral theses
|
Views |
887 |