MYC and EIF3H Coamplification significantly improve response and survival of non-small cell lung cancer patients (NSCLC) treated with gefitinib.
BACKGROUND
We investigated the incidence of eukaryotic translation initiation factor 3 subunit H (EIF3H) and MYC amplification in non-small cell lung cancer (NSCLC) patients, and whether MYC/EIF3H increased gene copy number affected response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors.


METHODS
Metastatic NSCLC patients (n = 54) treated with gefitinib were analyzed for the genomic content of EIF3H and MYC genes by fluorescence in situ hybridization (FISH) using a custom-designed 3-color DNA probe set.


RESULTS
Amplification of EIF3H (ratio EIF3H/CEP8 >2), was observed in 10 cases (18.5%), and MYC was coamplified in all. MYC amplification without coamplification of EIF3H was observed in 2 cases (3.7%). Receiver operating characteristic analysis was conducted to identify the cutoff for MYC and EIF3H copy number best discriminating sensitive and resistant populations. MYC FISH positive patients (MYC+, mean > or =2.8) had a significantly higher response rate (p = 0.003), longer time to progression (p = 0.01) and overall survival (OS: p = 0.02) than MYC- (mean <2.8). Similarly, EIF3H FISH positive patients (EIF3H+, mean > or =2.75) had a significantly higher response rate (p = 0.002), longer time to progression (p = 0.01) and OS (p = 0.01) than EIF3H- (mean <2.75).


CONCLUSIONS
Our results indicate that MYC and EIF3H are frequently coamplified in NSCLC and that a high copy number correlates with increased epidermal growth factor receptor tyrosine kinase inhibitors sensitivity.
Cappuzzo
Federico
F
Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy. federico.cappuzzo@humanitas.it
Varella-Garcia
Marileila
M
Rossi
Elisa
E
Gajapathy
Sujatha
S
Valente
Marialuisa
M
Drabkin
Harry
H
Gemmill
Robert
R
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D016259:Genes, myc; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D039621:Eukaryotic Initiation Factor-3; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib