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Background: The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients., Methods: We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model., Results: Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend = 9.62 × 10(-7)), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors., Conclusions: Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival., Impact: Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients., (©2015 American Association for Cancer Research.)

Purpose: Mouse double minute 4 (MDM4), a homolog of MDM2, is one of the key negative regulators of p53, and its amplification or overexpression contributes to carcinogenesis by inhibiting the p53 tumor suppressor activity. We investigated the association between MDM4 polymorphisms and the risk of squamous cell carcinoma of the head and neck (SCCHN)., Methods: We genotyped three MDM4 tagging polymorphisms, two in the 3' untranslated region (rs11801299G>A and rs10900598G>T) and one in intron 1 (rs1380576C>G), in a case-control study of 1075 non-Hispanic white SCCHN patients and 1079 cancer-free controls, and evaluated their associations with SCCHN risk., Results: Although none of these three polymorphisms individually had a statistically significant effect on the risk of SCCHN, nor did their combined number of putative risk genotypes (i.e. rs11801299GG, rs1380576CG+GG, and rs10900598GG) [odds ratio (OR)=1.16; 95% confidence interval (95% CI) =0.93-1.45], we found that individuals with 1-3 risk genotypes had statistically significant increased risk of oropharyngeal cancer (OR=1.32; 95% CI=1.00-1.73), particularly for those with T1-2 stage (OR=1.40; 95% CI=1.02-1.94), those with regional lymph node metastases (N1-3) (OR=1.44; 95% CI=1.07-1.95), and those with late stages (III and IV) (OR=1.34; 95% CI=1.01-1.77)., Conclusion: These results suggest that the joint effect of MDM4 variants may contribute to the risk of oropharyngeal cancer in non-Hispanic whites. Additional studies are warranted to unravel whether the particular stage distribution of oropharyngeal cancer with the strongest association (T1-2, N1-3, and III-IV) is a possible link with human papillomavirus-related oropharyngeal cancers.

In a hospital-based case-control study of 805 non-Hispanic whites with cutaneous melanoma and 841 cancer-free age-, sex- and ethnicity-matched control subjects, 3 VDR polymorphisms (i.e., TaqI, BsmI and FokI) were genotyped using blood samples collected between 1994 and 2006. We tested the hypothesis that the haplotypes and combined genotypes of these polymorphisms were associated with melanoma risk by interacting with known risk factors. Haplotypes t-B-F (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.34-0.80) and t-B-f (adjusted OR, 0.51; CI, 0.27-0.94) were associated with a reduced risk when compared to T-b-f. The combined genotypes Tt+tt/Bb+BB/Ff+ff (adjusted OR, 0.69; CI, 0.52, 0.90) and Tt+tt/Bb+BB/FF (adjusted OR, 0.58; CI, 0.43, 0.78) were also associated with reduced risk, whereas the combined genotype TT/Bb+BB/Ff+ff genotype (adjusted OR, 2.35; CI, 1.13, 4.98) was associated with increased risk when compared to TT/bb/Ff+ff genotypes. On multivariate analysis, only the TaqI polymorphism was an independent risk factor, while the FokI polymorphism interacted with skin color (p = 0.029), moles (p = 0.017) and first-degree relatives with any cancer (p = 0.013) in modifying risk. Together, these findings suggest that VDR polymorphisms may directly affect or modify the risk associated with known melanoma risk factors. Larger, population-based studies are needed to replicate our findings., ((c) 2008 Wiley-Liss, Inc.)

Although tobacco and alcohol use are the major risk factors, folate deficiency has been implicated in the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) in the folate metabolic pathway are associated with SCCHN risk. In a hospital-based case-control study of 721 SCCHN cases and 1,234 controls of non-Hispanic Whites, frequency matched by age, sex, and smoking status, we genotyped the MTR A2756G and MTRR G66A polymorphisms. We found that the MTR variant AG and AG/GG genotypes were associated with a significantly increased SCCHN risk [adjusted odd ratio (OR), 1.31; 95% confidence interval (95% CI), 1.07-1.60 for AG and OR, 1.28; 95% CI, 1.05-1.56 for AG/GG] compared with the AA genotype. In contrast, the MTRR variant AA genotype was associated with a significantly decreased SCCHN risk (OR, 0.68; 95% CI, 0.52-0.90) compared with the 66GG genotype. When the two polymorphisms were evaluated together by the number of risk alleles, the SCCHN risk was significantly increased in a dose-dependent manner (P(trend) = 0.002). The risk of SCCHN was 1.47 (95% CI, 1.08-1.99) for one risk allele, 1.67 (95% CI, 1.23-2.27) for two risk alleles, and 1.74 (95% CI, 1.18-2.54) for three or four risk alleles compared with the wild-type (0 risk allele) genotype. In conclusion, our data provide evidence that support the association between the MTR A2756G and MTRR G66A polymorphisms and SCCHN risk and that these two polymorphisms may have a joint effect on risk of SCCHN.

Oxidative damage is an important factor in prostate carcinogenesis, and overexpression of human MutT homolog (hMTH), a repair gene that removes oxidative damage, is a molecular marker of cellular oxidative stress. Therefore, we tested the hypothesis that overexpression of hMTH in unaffected (normal) surrogate tissue is associated with risk of prostate cancer in a pilot study of 51 patients with diagnosed prostate cancer and 50 age- and ethnicity-matched controls. Total RNA was extracted from phytohemagglutinin-stimulated peripheral blood lymphocytes of these subjects. We performed the real-time reverse transcription-polymerase chain reaction assay to evaluate the relative mRNA expression of three oxidative-damage-repair genes, human MutM homolog (hMMH), hMTH, and human MutY homolog (hMYH), with beta-actin and human O(6)-methylguanine DNA methyltransferase (hMGMT) as the internal controls. The relative gene expression levels of hMMH and hMTH were borderline higher in the cases than in controls (15.3% and 28.8% higher, respectively; P = 0.046 and P = 0.035, respectively), whereas no increase was observed for hMYH and hMGMT. With the median of the controls' values as the cutoff point, we observed that a high expression level of hMTH, but not of other genes, was associated with a significantly increased risk of prostate cancer (odds ratio = 2.62; 95% confidence interval = 1.13-6.75) after adjustment for age and ethnicity. These results suggested that increased expression of hMTH in peripheral lymphocytes may be a risk factor for prostate cancer and support our priori hypothesis. Although our findings were biologically plausible and consistent with the literature, they were preliminary and need to be confirmed in larger studies. In addition, a correlation between the expression level of hMTH and the level of oxidative DNA damage in the target tissues needs to be established as well., (Copyright 2003 Wiley-Liss, Inc.)