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Common Genetic Variation in TP53 Is Associated with Lung Cancer Risk and Prognosis in African Americans and Somatic Mutations in Lung Tumors

¹ Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland; ² Department of Surgery I, Nippon Medical School Hospital, Tokyo, Japan; ³ Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; ⁴ Advanced Technology Center, Intramural Research Support Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland; ⁵ Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research; and ⁶ Department of Cancer Epidemiology and Genetics, National Cancer Institute; Rockville, Maryland

Requests for reprints: Curtis C. Harris, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Room 3068, Building 37, 37 Convent Drive, Bethesda, MD 20892-4258. Phone: 301-496-2048; Fax: 301-496-0497. E-mail: Curtis_Harris{at}nih.gov

Lung cancer is primarily caused by tobacco smoking, but susceptibility is likely modified by common genetic variation. In response to many forms of cellular stress, including DNA damage, the p53 protein functions to induce cell cycle arrest, DNA repair, senescence, or apoptosis. We hypothesized that common TP53 haplotypes modulate pathways of lung carcinogenesis and lung cancer susceptibility or prognosis. To investigate our hypothesis, 14 polymorphisms in TP53, including haplotype tagging and coding single nucleotide polymorphisms, were genotyped in two studies from the greater Baltimore, Maryland area. One study is a case-control study and the second is a case-only study for which TP53 mutational spectra data are available. African Americans with Pro-T-A-G-G haplotypes of the combined TP53 polymorphisms TP53_01 (rs1042522), TP53_65 (rs9895829), TP53_66 (rs2909430), TP53_16 (rs1625895), and TP53_11 (rs12951053) had both an increased risk for lung cancer (odds ratio, 2.32; 95% confidence interval, 1.18-4.57) and a worsened lung cancer prognosis (hazards ratio, 2.38; 95% confidence interval, 1.38-4.10) compared with those with Arg-T-A-G-T haplotypes. No associations of TP53 polymorphisms with lung cancer were observed in Caucasians. In the case-only study, several polymorphisms in TP53 and TP53 haplotypes, overlapping regions of TP53 associated with risk and prognosis in African Americans, were associated with increased odds of somatic TP53 mutation in lung tumors in Caucasians. In conclusion, common genetic variation in TP53 could modulate lung cancer pathways, as suggested by the association with lung cancer in African Americans and somatic TP53 mutation frequency in lung tumors. (Cancer Epidemiol Biomarkers Prev 2007;16(2):214–22)

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