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)

A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been found to be associated with tumor formation. Publication of this null report is important because an association between MDM2 SNP309 and lung cancer was previously reported in two independent studies. Our findings suggest that MDM2 SNP309 is not a strong factor in lung carcinogenesis. In addition, this is the first MDM2 SNP309 report on a population consisting of Caucasians in the United States and African-Americans. A strength of the study design is that the controls consist of both population and hospital controls. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1559 -61)

The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g. G:C-->T:A mutations in TP53 are more frequently observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5-8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793 and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53-mediated apoptosis, were modestly associated with G:C-->T:A mutations in TP53 in lung tumors [Asp/Asn312 + Asn/Asn312 and/or Lys/Gln751 + Gln/Gln751 versus Asp/Asp312 + Lys/Lys751; odds ratio (OR) 2.73, 95% confidence interval (CI) 0.98-7.61], consistent with the role of this protein in repair of bulky carcinogen-DNA adducts. In addition, a TP53 polymorphism (Arg72Pro, rs1042522) with a known role in the efficiency of apoptosis was also associated with the presence of a TP53 mutation (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.25, 95% CI 1.21-4.17) or a G:C-->T:A mutation in TP53 (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.42, 95% CI 0.97-6.04). An interaction between the XPD variant alleles (Asn312 and Gln751) and the TP53 Pro72 allele was observed for TP53 mutations (any TP53 mutation P(int) = 0.027, G:C-->T:A TP53 mutation P(int) = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectra in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.

Folate deficiency has been implicated in the etiology of stomach cancer through abnormal DNA methylation and disrupted DNA synthesis and repair. Enzyme-coding genes involved in folate metabolism are often polymorphic. In a population-based study of 305 cases and 427 controls in Warsaw, Poland, we evaluated the risk of stomach cancer in relation to polymorphisms in folate-metabolizing genes, including MTHFR (Ex5+79C>T and Ex8À62A>C), MTR (Ex26À20A>G), and MTRR (Ex2À64A>G, Ex5+123C>T, Ex15+572C>T, Ex15À405A>T, Ex9À85C>T, Ex15À526G>A, and Ex14+14C>T). Polymorphisms in the MTHFR gene were not associated with stomach cancer risk. No notable effect was found for polymorphisms in MTR or MTRR either, although MTR Ex26À20 A>G and MTRR Ex5+123C>T polymorphisms were associated with a borderline increased risk of stomach cancer (MTR Ex26À20A>G, AG/GG versus AA: odds ratio, 1.35; 95% confidence interval, 0.96-1.90; MTRR Ex5+123C>T, CT/TT versus CC: odds ratio, 1.30; 95% confidence interval, 0.93-1.82). We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption. Our study did not identify strong genetic determinants in the folate metabolism pathway for stomach cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):115 -21)

No abstract