Exon 19 of EGFR mutation in relation to the CA-repeat polymorphism in intron 1.
Epidermal growth factor receptor (EGFR) mutations in lung cancer enhance tyrosine kinase activity and increase sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of the EGFR gene is therefore indispensable for predicting gefitinib response. We investigated a CA-repeat polymorphism in the EGFR gene related to EGFR mutations. Because an increasing number of CA-repeats at intron 1 of the EGFR gene has been reported to reduce transcription activity, we examined the relationship between EGFR mutations and this CA-repeat polymorphism. EGFR mutations at exon 19 were closely associated with shorter CA-repeat length in the shorter allele, but this was not the case for EGFR mutations at exons 18 or 21. Increased intrinsic EGFR mRNA expression in non-cancerous lung tissues from lung adenocarcinoma patients was also significantly associated with shorter CA-repeat length. A higher frequency of EGFR mutations at exon 19 was associated with shorter CA-repeat length only in patients with high levels of EGFR mRNA expression. To determine the phenotypes of cells possessing shorter CA-repeats, an in vitro study using human bronchial epithelial cells with different CA-repeat lengths was performed; more rapid cell growth and activated EGF/EGFR signaling were found more often in the cells having both shorter CA-repeats and increased EGFR mRNA expression. These results suggest that CA-repeat length in the EGFR gene may be a genetic factor related to cancer in the case of EGFR mutations at exon 19. The mechanism likely involves enhanced intrinsic expression of EGFR mRNA and activated EGF/EGFR signaling that accompany shorter CA-repeats.
Sueoka-Aragane
Naoko
N
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. sueokan@cc.saga-u.ac.jp
Imai
Kazue
K
Komiya
Kazutoshi
K
Sato
Akemi
A
Tomimasu
Rika
R
Hisatomi
Takashi
T
Sakuragi
Toru
T
Mitsuoka
Masahiro
M
Hayashi
Shinichiro
S
Nakachi
Kei
K
Sueoka
Eisaburo
E
D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary; D000368:Aged; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000556:secondary; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000556:secondary; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000235:genetics; D018900:Dinucleotide Repeats / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016066:Pleural Effusion, Malignant / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000556:secondary
D004273:DNA, Neoplasm; D012333:RNA, Messenger; D066246:ErbB Receptors