Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma.
A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P < 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors.
Sheu
Jim Jinn-Chyuan
JJ
Graduate Institute of Chinese Medical Science, Taichung, Taiwan.
Hua
Chun-Hung
CH
Wan
Lei
L
Lin
Ying-Ju
YJ
Lai
Ming-Tsung
MT
Tseng
Hsien-Chang
HC
Jinawath
Natini
N
Tsai
Ming-Hsui
MH
Chang
Nai-Wen
NW
Lin
Chin-Fen
CF
Lin
Chyi-Chyang
CC
Hsieh
Lie-Jiau
LJ
Wang
Tian-Li
TL
Shih
Ie-Ming
IeM
Tsai
Fuu-Jen
FJ
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D001115:Arecoline; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015854:Up-Regulation
D002273:Carcinogens; D001115:Arecoline; D015112:4-Nitroquinoline-1-oxide; D066246:ErbB Receptors