The close correlation between 8-hydroxy-2'-deoxyguanosine and epidermal growth factor receptor activating mutation in non-small cell lung cancer.
Patients with non-small cell lung cancer harboring mutations in the epidermal growth factor receptor gene, including delE746-A750 and L858R, are highly sensitive to therapy with epidermal growth factor receptor-targeting drugs, such as gefitinib and erlotinib, in comparison with those harboring wild-type epidermal growth factor receptor. It remains unclear how such epidermal growth factor receptor mutations are induced. In this study, we examined whether 8-hydroxy-2'-deoxyguanosine, a representative oxygen nucleotide of DNA, could play a role in activating mutations of the epidermal growth factor receptor gene and also whether Y-box binding protein-1 and 8-oxoguanine DNA glycosylase that are involved in repair of oxidative stimuli-induced DNA damages could play any role in epidermal growth factor receptor activating mutations. Immunohistochemistry was used to evaluate the expression of 8-hydroxy-2'-deoxyguanosine, Y-box binding protein-1, and 8-oxoguanine DNA glycosylase in patients with non-small cell lung cancer (N = 170). We analyzed mutations of delE746-A750 and L858R in the epidermal growth factor receptor gene using peptide nucleic acid-locked nucleic acid polymerase chain reaction clamping. In non-small cell lung cancer patients, nuclear 8-hydroxy-2'-deoxyguanosine expression was strongly associated with these epidermal growth factor receptor mutations. Furthermore, nuclear expression of Y-box binding protein-1 was inversely associated with epidermal growth factor receptor mutations; but nuclear expression of 8-oxoguanine DNA glycosylase was not. Among 51 patients who were treated with gefitinib, progression-free survival was substantially better when 8-hydroxy-2'-deoxyguanosine expression was positive, when epidermal growth factor receptor mutations were present, and when nuclear Y-box binding protein-1 expression was negative. Thus, activating mutations of the epidermal growth factor receptor gene in non-small cell lung cancer were closely associated with a decrease in the damage repair process for 8-hydroxy-2'-deoxyguanosine in oxidized DNA.
Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011, Japan.
Akihiko
A
Kawahara
Koichi
K
Azuma
Satoshi
S
Hattori
Kazutaka
K
Nakashima
Yuji
Y
Basaki
Jun
J
Akiba
Sinzo
S
Takamori
Hisamichi
H
Aizawa
Takashi
T
Yanagawa
Hiroto
H
Izumi
Kimitoshi
K
Kohno
Suminori
S
Kono
Masayoshi
M
Kage
Michihiko
M
Kuwano
Mayumi
M
Ono
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000096:biosynthesis; D004260:DNA Repair; D003839:Deoxyadenosines / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000627:therapeutic use; D012189:Retrospective Studies; D051840:Y-Box-Binding Protein 1 / Q000096:biosynthesis
C436623:8-hydroxy-2'-deoxyadenosine; D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D011799:Quinazolines; D051840:Y-Box-Binding Protein 1; D066246:ErbB Receptors; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D000077156:Gefitinib