Genetic susceptibility of lung cancer associated with common variants in the 3' untranslated regions of the adenosine triphosphate-binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export.
BACKGROUND
Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NKK) is a well defined carcinogen that can induce lung cancer. Genetic polymorphisms in its disposition pathways could modify the risk of developing lung cancer. The authors of this report previously catalogued the sequence variations of the adenosine triphosphate-binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export in the Chinese population and screened out common variants with potential function in their 5' flanking and 3' untranslated regions. The objective of the current study was to test the hypothesis that these common variants are associated with lung cancer risk.


METHODS
The genotyping analyses for 6 common regulatory variants (reference single-nucleotide polymorphism 4728709 [rs4728709] and rs2188524 in the 5' flanking region of ABCB1 and rs3842 in its 3' untranslated region; rs3743527, rs212090, and rs212091 in the 3' untranslated region of ABCC1) was conducted in a case-control study of 500 patients with incident lung cancer and 517 cancer-free controls in a Chinese population.


RESULTS
Compared with the wild adenosine/adenosine (A/A) genotype, the variant rs3842 genotype (adenosine/guanosine [A/G] + G/G) of ABCB1 was associated with a statistically significant increased risk of developing lung cancer (odds ratio [OR]. 1.36; 95% confidence interval [95% CI], 1.06-1.76). Also evident was the association between cancer susceptibility and the variant rs212090 genotype (adenosine/thymidine [A/T] + T/T) of ABCC1 (OR, 1.37; 95% CI, 1.03-1.83). Haplotype-based association analysis also emphasized that 2 common haplotypes carrying the culprit alleles of the 2 single-nucleotide polymorphisms were associated with an increased risk of cancer. In addition, stratification analysis demonstrated a remarkable association of ABCB1 rs3842 with the risk of cancer manifested in women (OR, 2.57; 95% CI, 1.36-4.85), in the histologic type of adenocarcinoma (OR, 1.42; 95% CI, 1.03-1.99), and in individuals aged <60 years (OR, 1.50; 95% CI, 1.05-2.14).


CONCLUSIONS
The current study demonstrated that common polymorphisms in the 3' untranslated region of ABCB1 and ABCC1 may contribute to the etiology of lung cancer, providing further support for the hypothesis that genetic components in the metabolism and the disposition of NNK may modify the risk of lung cancer, especially in lung adenocarcinoma among women. 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.
Wang
Haijian
H
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.
Jin
Guangfu
G
Wang
Haifeng
H
Liu
Gaifen
G
Qian
Ji
J
Jin
Li
L
Wei
Qingyi
Q
Shen
Hongbing
H
Huang
Wei
W
Lu
Daru
D
D020413:3' Untranslated Regions; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D002273:Carcinogens; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009602:Nitrosamines; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects
D020413:3' Untranslated Regions; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002273:Carcinogens; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009602:Nitrosamines; C513055:ABCB1 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C421109:multidrug resistance-associated protein 1