Functional promoter -1271G>C variant of HSPB1 predicts lung cancer risk and survival.
PURPOSE Heat-shock protein 27 (Hsp27), encoded by HSPB1, plays crucial roles in tumorigenesis and cell survival and is reported to be an independent prognosis marker for cancer. We hypothesized that genetic variants of the HSPB1 gene may be associated with lung cancer susceptibility and survival. PATIENTS AND METHODS We first resequenced the full-length HSPB1 gene and then genotyped three selected tag single nucleotide polymorphisms (SNPs) in 1,152 paired Chinese lung cancer patient cases and controls. Another 500 paired patient cases and controls were used for replication. We also evaluated the roles of these tagSNPs in the overall survival of 248 patients with advanced non-small-cell lung cancer (NSCLC), and validated the results in another 335 patients with advanced NSCLC. The genotype-phenotype correlation was assessed in 309 workers with occupational exposure to polycyclic-aromatic hydrocarbons (PAHs) as well as by luciferase reporter assay and Western blotting analysis. RESULTS The -1271C allele was associated with a significantly increased lung cancer risk in the two independent patient case-control studies (P < .05 for both), but it conferred a favorable survival for patients with advanced NSCLC in two independent cohorts (adjusted hazard ratio, 0.66 and 0.75, respectively). The occupational PAH-exposed workers carrying the -1271C allele showed higher DNA damage levels than those with the -1271G allele (P = .027). Furthermore, the -1271C allele significantly decreased luciferase activity in four cell lines and resulted in lower Hsp27 expression levels in normal lung tissues when compared with -1271G allele (P < .05). CONCLUSION The functional HSPB1 promoter -1271G>C variant may affect lung cancer susceptibility and survival by modulating endogenous Hsp27 synthesis levels.
Institute of Occupational Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan 430030, Hubei, China.
Huan
H
Guo
Yun
Y
Bai
Ping
P
Xu
Zhibin
Z
Hu
Li
L
Liu
Fang
F
Wang
Guangfu
G
Jin
Feng
F
Wang
Qifei
Q
Deng
Yixiao
Y
Tu
Maohui
M
Feng
Daru
D
Lu
Hongbing
H
Shen
Tangchun
T
Wu
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000368:Aged; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000556:secondary; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D016273:Occupational Exposure; D011084:Polycyclic Aromatic Hydrocarbons; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D015996:Survival Rate
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011084:Polycyclic Aromatic Hydrocarbons; D008156:Luciferases