Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. [2].
Nature Genetics (Impact Factor: 29.35). 11/2012; DOI: 10.1038/ng.2456
Source: PubMed


To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.

Download full-text


Available from: Keitaro Matsuo, Oct 13, 2015
1 Follower
118 Reads
  • Source
    • "We identified previous genome-wide studies relevant to our research, such as those conducted in breast cancer and lung cancer [50]–[55]. However, these studies were not included in our analysis because their raw data was not available. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background CXCL12 is a small chemotactic cytokine belonging to the CXC chemokine family expressed in various organs. It contributes to the migration, invasion and angiogenesis of cancer cells. Recently, the CXCL12 G801A polymorphism was shown to be associated with an increased risk of various kinds of cancers, but the results were too inconsistent to be conclusive. Methods To solve the problem of inadequate statistical power and conflicting results, a meta-analysis of published case-control studies was performed, including 4,435 cancer cases and 6,898 controls. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to determine the strength of association between CXCL12 G801A polymorphism and cancer risk. Results A significant association between CXCL12 G801A polymorphism and cancer risk was found under all genetic models. Further, subgroup analysis stratified by ethnicity suggested a significant association between CXCL12 G801A polymorphism and cancer risk in the Asian subgroup under all genetic models. However, in the Caucasian subgroup, a significant association was only found under an additive genetic model and a dominant genetic model. The analysis stratified by cancer type found that CXCL12 G801A polymorphism may increase the risk of breast cancer, lung cancer, and “other” cancers. Based on subgroup stratified by source of controls, a significant association was observed in hospital-based studies under all genetic models. Conclusions The CXCL12 G801A polymorphism is associated with an increased risk of cancer based on current published data. In the future, large-scale well-designed studies with more information are needed to better estimate possible gene-gene or gene-environment interactions.
    PLoS ONE 09/2014; 9(9):e108953. DOI:10.1371/journal.pone.0108953 · 3.23 Impact Factor
  • Source
    • "The hypothesis underlying our SNP analysis was that if SNPs were associated with cancer, the proportions of different alleles would be different in cancer and normal groups. Previously, rs7086803 at 10q25.2, rs9387478 at 6q22.2 and rs2395185 at 6p21.32 were identified as lung cancer susceptibility loci in never-smoking women in Asia [40]. In this study, we identified another 4 SNPs (rs1700874, rs10248565, rs11761619, and rs9316119) that were significantly (P <0.01) associated with lung cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous efforts have been made to elucidate the etiology and improve the treatment of lung cancer, but the overall five-year survival rate is still only 15%. Although cigarette smoking is the primary risk factor for lung cancer, only 7% of female lung cancer patients in Taiwan have a history of smoking. Since cancer results from progressive accumulation of genetic aberrations, genomic rearrangements may be early events in carcinogenesis. In order to identify biomarkers of early-stage adenocarcinoma, the genome-wide DNA aberrations of 60 pairs of lung adenocarcinoma and adjacent normal lung tissue in non-smoking women were examined using Affymetrix Genome-Wide Human SNP 6.0 arrays. Common copy number variation (CNV) regions were identified by >=30% of patients with copy number beyond 2 +/- 0.5 of copy numbers for each single nucleotide polymorphism (SNP) and at least 100 continuous SNP variant loci. SNPs associated with lung adenocarcinoma were identified by McNemar's test. Loss of heterozygosity (LOH) SNPs were identified in >=18% of patients with LOH in the locus. Aberration of SNP rs10248565 at HDAC9 in chromosome 7p21.1 was identified from concurrent analyses of CNVs, SNPs, and LOH. The results elucidate the genetic etiology of lung adenocarcinoma by demonstrating that SNP rs10248565 may be a potential biomarker of cancer susceptibility.
    Journal of Biomedical Science 03/2014; 21(1):24. DOI:10.1186/1423-0127-21-24 · 2.76 Impact Factor
  • Source
    • "In this study, we did not confirm the previously reported SNPs from GWA studies in Asian population and found inconsistent results among several reports (21-25). A study of lung cancer in never-smoking Asian women (21) demonstrated that common genetic variants (rs2736100) in the TERT-CLPTM1L locus on chromosome 5p15.33 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer in never-smokers ranks as the seventh most common cause of cancer death worldwide, and the incidence of lung cancer in non-smoking Korean women appears to be steadily increasing. To identify the effect of genetic polymorphisms on lung cancer risk in non-smoking Korean women, we conducted a genome-wide association study of Korean female non-smokers with lung cancer. We analyzed 440,794 genotype data of 285 cases and 1,455 controls, and nineteen SNPs were associated with lung cancer development (P < 0.001). For external validation, nineteen SNPs were replicated in another sample set composed of 293 cases and 495 controls, and only rs10187911 on 2p16.3 was significantly associated with lung cancer development (dominant model, OR of TG or GG, 1.58, P = 0.025). We confirmed this SNP again in another replication set composed of 546 cases and 744 controls (recessive model, OR of GG, 1.32, P = 0.027). OR and P value in combined set were 1.37 and < 0.001 in additive model, 1.51 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model. The effect of this SNP was found to be consistent only in adenocarcinoma patients (1.36 and < 0.001 in additive model, 1.49 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model). Furthermore, after imputation with HapMap data, we found regional significance near rs10187911, and five SNPs showed P value less than that of rs10187911 (rs12478012, rs4377361, rs13005521, rs12475464, and rs7564130). Therefore, we concluded that a region on chromosome 2 is significantly associated with lung cancer risk in Korean non-smoking women.
    Journal of Korean medical science 06/2013; 28(6):840-7. DOI:10.3346/jkms.2013.28.6.840 · 1.27 Impact Factor
Show more