Genetic polymorphisms in the endothelial nitric oxide synthase gene correlate with overall survival in advanced non-small-cell lung cancer patients treated with platinum-based doublet chemotherapy.
BACKGROUND
Nitric oxide (NO) is a free radical that is involved in carcinogenesis. Endothelial NO, synthesized from L-arginine by endothelial NO synthase (eNOS), inhibits apoptosis and promotes angiogenesis, tumor cell proliferation and metastasis. The aim of this study was to evaluate the influence of polymorphisms in the eNOS gene on prognosis of patients with advanced stage non-small-cell lung cancer (NSCLC).


METHODS
Unresectable, chemotherapy naïve stage III or IV NSCLC patients who were treated with standard platinum-containing doublet regimens were analyzed. All individuals were genotyped for the single-nucleotide polymorphism G894T in exon 7 of the eNOS gene and for a variable number of tandem repeats (VNTR) polymorphism in intron 4 that results in a rare smaller allele (a) and a common larger allele (b), to investigate the association between these polymorphisms and clinical outcomes. The primary endpoint was correlation with overall survival.


RESULTS
From October 2004 to December 2007, 108 patients (male/female, 66/42; Stage IIIA/IIIB/IV, 6/30/72) aged 29-77 years (median 63) with good performance status were consecutively enrolled in this study. Using Kaplan-Meier estimates, we showed that 5-year overall survival was significantly increased in patients carrying the VNTR a-allele compared with VNTR b/b patients (P = 0.015). In multivariate Cox proportional hazard analysis, the VNTR polymorphism was an independent prognostic factor for survival.


CONCLUSIONS
The results support the role of the VNTR polymorphism in intron 4 as a marker for survival in patients with advanced stage NSCLC who are candidates for standard chemotherapy.
Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima Minami-machi, Chuo-ku, Kobe, Japan. jp.shirofujita@gmail.com
Shiro
S
Fujita
Katsuhiro
K
Masago
Yukimasa
Y
Hatachi
Akiko
A
Fukuhara
Akito
A
Hata
Reiko
R
Kaji
Young Hak
YH
Kim
Tadashi
T
Mio
Michiaki
M
Mishima
Nobuyuki
N
Katakami
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D009367:Neoplasm Staging; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D017239:Paclitaxel / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015996:Survival Rate; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D016190:Carboplatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D017239:Paclitaxel; D000093542:Gemcitabine