RGD Reference Report - ATM sequence variants associate with susceptibility to non-small cell lung cancer. - Rat Genome Database

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ATM sequence variants associate with susceptibility to non-small cell lung cancer.

Authors: Yang, Hushan  Spitz, Margaret R  Stewart, David J  Lu, Charles  Gorlov, Ivan P  Wu, Xifeng 
Citation: Yang H, etal., Int J Cancer. 2007 Nov 15;121(10):2254-9. doi: 10.1002/ijc.22918.
RGD ID: 150383340
Pubmed: PMID:17582598   (View Abstract at PubMed)
PMCID: PMC3477817   (View Article at PubMed Central)
DOI: DOI:10.1002/ijc.22918   (Journal Full-text)

ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case-control analysis of 556 Caucasian non-small-cell lung cancer (NSCLC) patients and 556 controls frequency-matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild-type allele-containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02-2.35) and 1.51 (0.99-2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation-Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25-0.96) compared with the common H1 haplotype. Compared with the H1-H2 diplotype, H2-H2 and H3-H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99-2.54) and 2.29 (1.05-5.00), respectively. We then evaluated genotype-phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild-type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation-induced olive tail moment (ATM08: 4.86 +/- 2.43 vs. 3.79 +/- 1.51, p = 0.04; ATM10: 5.14 +/- 2.37 vs. 3.79 +/- 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk-conferring variants might act through down-regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lung non-small cell carcinoma susceptibilityIAGP 150383340DNA:SNPs more ...RGD 
lung non-small cell carcinoma susceptibilityISOATM (Homo sapiens)150383340; 150383340DNA:SNPs more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Abnormality of DNA repair susceptibilityIAGP 150383340DNA:SNPs:introns: (rs227060 and rs170548) (human)RGD 
Non-small cell lung carcinoma susceptibilityIAGP 150383340DNA:SNPs more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)


Additional Information