Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer.
BACKGROUND
Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease.


METHODS
Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.


RESULTS
EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.


CONCLUSIONS
Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.
Department of Clinical Oncology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Turin, Italy. caterina.peraldoneia@ircc.it
Caterina
C
Peraldo-Neia
Giorgia
G
Migliardi
Maurizia
M
Mello-Grand
Filippo
F
Montemurro
Raffaella
R
Segir
Ymera
Y
Pignochino
Giuliana
G
Cavalloni
Bruno
B
Torchio
Luciano
L
Mosso
Giovanna
G
Chiorino
Massimo
M
Aglietta
D000368:Aged; D004252:DNA Mutational Analysis; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
D066246:ErbB Receptors; D051858:Forkhead Transcription Factors; D007610:Kallikreins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017430:Prostate-Specific Antigen; D014157:Transcription Factors; C073492:ABCC4 protein, human; C472771:EAF2 protein, human; C112743:FOXC1 protein, human; C549870:KLK3 protein, human
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