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【科普】ATP-结合盒转运蛋白基因变异患肺癌风险
ATP-结合盒转运蛋白基因变异患肺癌风险较高
December 22, 2008 — Chinese researchers have found variants of 2 genes that increase lung cancer susceptibility. Two ATP-Binding Cassette transporter genes — ABCB1 and ABCC1 — encode transporter molecules that eliminate a variety of carcinogens from lung cells. The study showed that the variants were particularly linked to lung cancer susceptibility in women and in patients younger than 60 years; the variants are also linked to adenocarcinoma more than to other types of lung cancer.
A carcinogenic substance found in tobacco and derived from nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces lung cancer in rodent studies. Phase 1 enzymes convert NNK from a procarcinogen to an active carcinogen in the human respiratory tract.
NNK metabolites stimulate DNA synthesis and cell division but are rendered less harmful by phase 2 enzymes and are then eliminated from lung cells by phase 3 transporters. Transport protein ABCC1 eliminates NNK metabolites from cells, whereas transport protein ABCB1 expels a variety of carcinogens absorbed via diet or cigarette smoke.
The new study, published online December 22 in Cancer, notes that ABC transporters "modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics.... [T]here is cumulating evidence that these efflux pumps are capable of transporting a vast and chemically diverse array of toxicants, including dietary and environmental carcinogens," state the authors. "It is likely that the transporters prevent harmful foreign substances from accumulating "in sensitive tissues such as the lung."
Led by Daru Lu, PhD, and Haijian Wang, PhD, from the State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, the investigation analyzed the link between variants in genes encoding ABCB1 and ABCC1 and risk for lung cancer. Dr. Wang is also affiliated with the Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, New Jersey.
The case-control study enrolled lung cancer patients (n = 500) and cancer-free control patients (n = 517) matched to case patients by sex, age, and urban or rural residence. Demographic information was obtained through a questionnaire. Genotypes were obtained from 5-mL blood samples, focusing on 3 common regulatory single nucleotide polymorphisms (SNPs) of ABCB1 and 3 SNPs of ABCC1.
Analysis of the difference in genotype distribution between case patients and control patients found that the G allele (A/G and G/G) of rs3842 of ABCB1 was associated with an increased occurrence of lung cancer, although statistical significance was marginal (P = .075); similarly, the T allele (A/T and T/T) of rs212090 of ABCC1 was more common in case patients than in control patients (P = .043). For both SNPs, risk allele homozygotes were relatively rare and were combined with heterozygotes for further analysis.
The combined A/G and G/G genotypes of ABCB1 rs3842 conveyed a significantly increased susceptibility to lung cancer compared with the A/A genotoype (P = .016; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.06 – 1.76). Likewise, the A/T and T/T genotypes of ABCC1 rs212090 demonstrated greater susceptibility than did the A/A genotype (P = .033; OR, 1.37; 95% CI, 1.03 – 1.83).
The assessment of demographic variables found the risk alleles of rs3842 to be strongly associated with increased occurrence of lung cancer in women (P = .003; OR, 2.57; 95% CI, 1.36 – 4.85), with individuals younger than 60 years (P = .025; OR, 1.50; 95% CI, 1.05 – 2.14), and with adenocarcinoma rather than squamous cell or other lung cancer types (P = .034; OR, 1.42; 95% CI, 1.03 – 1.99).
NNK, the levels of which in cigarette smoke increased nearly 50% from 1978 to 1992, has been previously linked with adenocarcinoma, Interestingly, the rates of adenocarcinoma have continued to increase in recent years, most notably in women.
Although "the current study may have some limitations because it was a hospital-based...study with a relatively small sample size," acknowledge the authors, their results "suggest that further functional studies are warranted to elucidate whether aberrant expression and dysfunction of ABC transporters for carcinogen export may play a role in the development of lung cancer."
Cancer. Published online December 22, 2008. [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-07-22 18:41
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