Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement.
We examined the association between N(e)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI.
Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26).
Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers.
This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development.
Cites: J Am Soc Nephrol. 2005 Aug;16(8):2363-7215930093
Cites: Ann N Y Acad Sci. 2005 Jun;1043:725-3316037299
Folate is hypothesized to be inversely associated with the risk of several cancers, but such a potential association has not been well studied for prostate cancer. Vitamin B-6, vitamin B-12, methionine, and alcohol can influence folate-related metabolism.
The objective was to investigate the associations between dietary factors of one-carbon metabolism and prostate cancer risk within the alpha-Tocopherol, beta-Carotene Cancer Prevention Study.
Of the cohort's 27 111 Finnish male smokers aged 50-69 y who had complete dietary data, 1270 had a diagnosis of incident prostate cancer between 1985 and 2002. Folate, vitamin B-6, vitamin B-12, methionine, and alcohol intakes were estimated from a 276-item modified dietary history questionnaire. Cox proportional hazard models, adjusted for age and vitamin supplement use, estimated relative risks (RR) and 95% CIs.
Vitamin B-6 intake was inversely associated with prostate cancer risk (RR for highest versus lowest quintile: 0.88; 95% CI: 0.72, 1.07; P for trend = 0.045), whereas vitamin B-12 intake was associated with significantly increased risk (RR = 1.36; 95% CI: 1.14, 1.96; P for trend = 0.01). No association between folate or alcohol intake and prostate cancer risk was observed. No differences were found in the above associations according to stage of disease or subgroups of several potential effect modifiers.
We found no convincing evidence for a protective role of one-carbon metabolism against prostate cancer, although these observations can be generalized only to smokers. The possible modest protective association with vitamin B-6 and the significantly elevated risk with vitamin B-12 intake warrant further investigation.
Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of N(e)-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case-cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985-1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38-1.22), P(trend) = 0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23-0.73), P(trend) = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers.
Cites: Am J Epidemiol. 1999 Mar 15;149(6):531-4010084242
The cytokine interleukin 8 (IL-8) may play a role in the pathogenesis of prostate cancer through the modulation of tumour immune response or enhanced angiogenesis. A common polymorphism of the IL-8 (-251) gene, which may affect the production level of the cytokine, has been inversely associated with a number of diseases, including prostate cancer. We examined the most representative single nucleotide polymorphisms (SNPs) for the IL-8 and its receptors (CXCR1 and CXCR2) genes, and conducted a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine if these SNPs are associated with susceptibility to and prognosis of prostate cancer. Using incidence density sampling, 584 cases of primary prostate cancer and 584 matched controls were selected. In this population, we observed no strong association between the SNPs for IL-8 -251 (A-->T), CXCR1 +860 (C-->G) and CXCR2 -1010 (A-->G) and either the subsequent risk of prostate cancer or individual prognostic factors among cases. Although none of the SNPs studied are likely to have major effects on prostate cancer susceptibility, a role for other polymorphisms associated within these genes cannot be excluded.
Homocysteine is associated with stroke, but it is not clear whether this relationship is causal. We examined the association between total serum homocysteine concentration (tHcy) and cerebral infarction in a cohort of Finnish male smokers.
This is a matched case-control study of 201 cases of cerebral infarction and 201 concurrently sampled age-matched controls nested in a cohort of 13 840 male smokers free of cardiovascular disease at the completion of the Alpha-Tocopherol and Beta-Carotene (ATBC) Cancer Prevention study. Conditional logistic regression was used to calculate odds ratios (ORs) and to adjust for confounding variables. An unmatched analysis was also performed.
The geometric mean tHcy was 13.3 micromol/L (95% CI, 12.6 to 13.9) in cases and 12.6 micromol/L (95% CI, 12.0 to 13.2) in controls (P=0.09). There was a graded increase in the OR of cerebral infarction per quartile increase in tHcy (OR, 1.0, 1.7, 1.9, 2.1; trend P=0.02; 201 case-control pairs) when adjusted for traditional risk factors. There was a similar trend in a subgroup of 120 case-control pairs for which further adjustment for lifestyle factors was possible (OR, 1.0, 1.9, 2.5, 2.2; trend P=0.07 in the matched analyses; OR, 1.0, 1.2, 1.9, 2.0; trend P=0.02 in the unmatched analyses). The adjusted OR per 1-SD increase in log-transformed tHcy (equivalent to 4.7 micromol) was 1.4 (95% CI, 1.1 to 1.7; P=0.01).
tHcy appears to predict cerebral infarction in Finnish male smokers.
Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC).
We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis.
Serum iron metrics were not associated with GCC, except for a potential "n"-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a "u"-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations.
We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency.
Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted.
Cancer Prevention Fellowship Program, Division of Cancer Prevention and Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, 37 Convent Drive, Building 37, Room 1106, Bethesda, MD 20892-4254, USA. email@example.com
Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2784-6
Genetic variations in xenobiotic metabolizing genes can influence susceptibility to many environmentally induced cancers. Inheritance of the N-acetyltransferase 1 allele (NAT1*10), linked with increased metabolic activation of pro-carcinogens, is associated with an increased susceptibility to many cancers in which cigarette- or meat-derived carcinogens have been implicated in their etiology. The role of NAT1*10 in prostate cancer is under studied. Although cigarette smoking is not considered a risk factor for prostate cancer, a recent review suggests it may play a role in disease progression. Consequently, we examined the association of NAT1*10 with prostate cancer risk, grade, and stage among 400 Finnish male smokers using a case-control study design. Following genotyping of 206 patients and 196 healthy controls, our results do not support the role of NAT1*10 in relation to prostate cancer risk (OR?=?1.28; 95% CI, 0.66-2.47), aggressive disease (OR?=?0.58; 95% CI, 0.13-2.67), or advanced disease (OR?=?1.19; 95% CI, 0.49-2.91).
Cites: Cancer Res. 1998 Aug 15;58(16):3603-109721868
Cites: Cancer Lett. 2000 Feb 28;149(1-2):53-6010737708
Cites: Drug Metab Dispos. 2000 Dec;28(12):1425-3211095579
Lead is classified as a probable human carcinogen. However, its role in renal cell cancer (RCC) has not been established. Calcium and vitamin D may off-set toxicity in vivo.
In this nested case-control study, whole blood lead, total serum calcium, and serum 25-hydroxyvitamin D levels were measured in blood drawn prior to diagnosis among male smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Single-nucleotide polymorphisms (SNP) in five genes (CALB1, TRPV5, TRPV6, VDR, and ALAD) related to lead toxicity or calcium transport were genotyped. Logistic and linear regressions were used to determine RCC risk and time to diagnosis (respectively), adjusting for other risk factors.
Among 154 newly diagnosed cases and 308 matched controls, RCC was associated with higher whole blood lead [OR = 2.0; 95% confidence interval (CI), 1.0-3.9; quartile 4 (Q4) vs. Q1, P(trend) = 0.022] and CALB1 rs1800645 (P(trend) = 0.025, minor 'T' allele frequency = 0.34). Higher total serum calcium (P(trend) = 0.001) was associated with reduced RCC risk. Total serum calcium and 25-hydroxyvitamin D levels did not alter the association observed with lead. Time from enrollment to RCC diagnosis was positively associated with serum calcium (P(trend) = 0.002) and 25-hydroxyvitamin D (P(trend) = 0.054) among cases.
Higher blood lead concentrations, below the 10 µg/dL level of concern, were associated with RCC, independent from serum calcium and CALB1 promoter polymorphism.
Increased risk of RCC is associated with lower serum calcium and higher whole blood lead in smokers. The clinical prognostic value of serum calcium and vitamin D in RCC should be further investigated.