Polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13 and MT2A do not contribute to breast, lung and colon cancer risk in polish population.

BACKGROUND: Matrix metalloproteinases (MMPs) and metallothioneins (MTs) are Zinc-related proteins which are involved in processes crucial for carcinogenesis such as angiogenesis, proliferation and apoptosis. Several single nucleotide polymorphisms (SNPs) in MMPs and MTs that affect genes expression have been associated with cancer risk, including breast, lung and colon. METHODS: The study group consisted of 648 unselected patients (299 with breast cancer, 199 with lung cancer, 150 with colon cancer) and 648 unaffected individuals. Five SNPs, rs1799750 in MMP-1, rs243865 in MMP-2, rs11568818 in MMP-7, rs2252070 in MMP-13 and rs28366003 in MT2A were genotyped and serum zinc (Zn) level was measured. The cancer risk was calculated using multivariable logistic regression with respect to Zn. RESULTS: None of the 5 tested polymorphisms showed a correlation with cancer risk in studied groups, although for MMP-2, MMP-7 and MT2A non-significant differences in genotypes frequencies among cases and controls were observed. CONCLUSIONS: Analyses of polymorphisms, rs1799750 in MMP-1, rs243865 in MMP-2, rs11568818 in MMP-7, rs2252070 in MMP-13 and rs28366003 in MT2A in relation to serum Zn level did not show significant association with breast, lung and colon cancer risk among polish patients. Further studies are needed to verify this observation.

BRCA1 promoter methylation in peripheral blood is associated with the risk of triple-negative breast cancer.

Methylation of the promoter of the BRCA1 gene in DNA derived from peripheral blood cells is a possible risk factor for breast cancer. It is not clear if this association is restricted to certain types of breast cancer or is a general phenomenon. We evaluated BRCA1 methylation status in peripheral blood cells from 942 breast cancer patients and from 500 controls. We also assessed methylation status in 262 paraffin-embedded breast cancer tissues. Methylation status was assessed using methylation-sensitive high-resolution melting and was categorized as positive or negative. BRCA1 methylation in peripheral blood cells was strongly associated with the risk of triple-negative breast cancer (TNBC) (odds ratio [OR] 4.70; 95% confidence interval [CI]: 3.13-7.07; p < 0.001), but not of estrogen-receptor positive breast cancer (OR 0.80; 95% CI: 0.46-1.42; p = 0.46). Methylation was also overrepresented among patients with high-grade cancers (OR 4.53; 95% CI: 2.91-7.05; p < 0.001) and medullary cancers (OR 3.08; 95% CI: 1.38-6.88; p = 0.006). Moreover, we detected a significant concordance of BRCA1 promoter methylation in peripheral blood and paired tumor tissue (p < 0.001). We found that BRCA1 promoter methylation in peripheral blood cells is associated with approximately five times greater risk of TNBC. We propose that BRCA1 methylation in blood-derived DNA could be a novel biomarker of increased breast cancer susceptibility, in particular for triple-negative tumors.

Influence of the selenium level on overall survival in lung cancer.

BACKGROUND: Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, the effect of this microelement on survival has not been studied. MATERIALS AND METHODS: We performed a prospective study of 302 patients diagnosed with lung cancer in Szczecin, Poland. Selenium concentration in serum was measured at the time of diagnosis and before treatment. All patients were followed for a maximum of 80 months or until death. Vital status was obtained from the Polish National Death Registry. RESULTS: Using Cox proportional hazard analysis, performed for all individuals with lung cancer, the hazard ratio (HR) for death from all causes was 1.25 (95% CI: 0.86-1.83, P = 0.99) for patients in the lowest tertile compared to those in the highest tertile of serum selenium levels. Among the patients with stage I disease this relationship was significant (HR-2.73; P = 0.01) for selenium level in tertile 1 (<57 µg/L) compared to tertile 3 (>69 µg/L, reference). The 80 months crude survival after diagnosis was 79.5% (95% CI: 68.5-92.4%) for individuals in the highest tertile and 58.1% (95% CI: 45.1-74.9%) for individuals in the lowest tertile with stage I lung cancer. CONCLUSION: These results suggest that in patients undergoing treatment for stage I lung cancer, serum selenium levels at the time of diagnosis (>69 µg/L) may be associated with improved overall survival.

Iron levels, genes involved in iron metabolism and antioxidative processes and lung cancer incidence.

BACKGROUND: Lung cancer is the most common adult malignancy accounting for the largest proportion of cancer related deaths. Iron (Fe) is an essential trace element and is a component of several major metabolic pathways playing an important role in many physiological processes. In this study we evaluated the association between Fe concentration in serum, iron metabolism parameters and genetic variaton in 7 genes involved in iron metabolism and anti-oxidative processes with the incidence of lung cancer in Poland. MATERIALS AND METHODS: The study included 200 lung cancer patients and 200 matched healthy control subjects. We analyzed serum iron concentration and iron metabolism parameters (TIBC, UIBC, serum ferritin and transferrin saturation), and genotyped seven variants in seven genes: HFE, TFR1, HAMP, TF, SOD2, CAT and GPX1. RESULTS: Lung cancer patients compared to their matched controls had significantly higher mean serum iron level (p = 0.01), ferritin level (p = 0.007) and TIBC (p = 0.006). Analysis revealed that higher concentration of iron and ferritin (IVth quartile) compared to the lower concentration (Ist quartile) was associated with over 2-fold increased lung cancer incidence. We also found that higher transferrin saturation (p = 0.01) and lower TIBC (p<0.01) are associated with better survival of lung cancer patients. The analysis of polymorphisms in iron related genes did not reveal a significant difference between lung cancer patients and controls. However, rs10421768 in HAMP showed a borderline statistically significant correlation with lung cancer risk (OR = 2.83, p = 0.05). CONCLUSIONS: The results of this case control study indicate that higher body iron represented by higher Fe and ferritin levels may be associated with lung cancer incidence. Rs10421768 in HAMP may be associated with about 3-times higher lung cancer risk. Higher Fe body content may be associated with better survival of lung cancer patients.

Serum selenium level and cancer risk: a nested case-control study.

BACKGROUND: Epidemiologic studies have demonstrated a relationship between selenium status and cancer risk among those with low selenium levels. It is of interest to prospectively evaluate the relationship between selenium and cancer among women who reside in a region with ubiquitously low selenium levels. METHODS: We performed a nested case-control study of baseline serum selenium levels and cancer risk using data and biological samples from 19,573 females that were participants in a biobanking initiative between 2010 and 2014 in Szczecin Poland. Cases included women with any incident cancer (n = 97) and controls (n = 184) were women with no cancer at baseline or follow-up. Serum selenium was quantified using mass spectroscopy. RESULTS: The odds ratio associated being below the cutoff of 70.0 µg/L compared to a level above 70.0 µg/L was 2.29 (95% CI 1.26-4.19; P = 0.007). The risks for women in the two middle categories were similar and suggests that the normal range be between 70 µg/L and 90 µg/L. There was evidence for an increased risk of cancer among women in the highest category of selenium levels (i.e., > 90 µg/L), but this association did not achieve statistical significance (OR = 1.63; 95%CI 0.63-4.19; P = 0.31). CONCLUSIONS: Results from this study suggest that suggest that the optimum serum level of selenium in women living in Poland should be between 70 µg/L and 90 µg/L.

Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population.

INTRODUCTION: Prostate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland. METHODS: The study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped. RESULTS: The mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 µg/l vs. 856.6±13.05 µg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07-9.37, p<0.01) was observed in 3rd quartile (>853.0-973.9 µg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19-4.82, p = 0.015). CONCLUSION: Our results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland.

Correction: Serum selenium levels and the risk of progression of laryngeal cancer.

[This corrects the article DOI: 10.1371/journal.pone.0184873.].

Serum selenium levels and the risk of progression of laryngeal cancer.

BACKGROUND: Observational studies have reported an inverse relationship between selenium status (blood or toenail) and the risk of laryngeal cancer; however, the impact of low serum selenium level on survival has not been evaluated. METHODS: We conducted a prospective study of 296 patients diagnosed with laryngeal cancer in Szczecin, Poland. Serum selenium was measured at diagnosis and prior to treatment. Patients were followed from the date of diagnosis to death at five years. Vital status was obtained by linkage to the Polish National Death Registry. RESULTS: The five-year survival after diagnosis was 82.0% (95% CI: 68% to 91%) for individuals in the highest quartile of serum selenium (> 66.8 µg/L) and was 28.6% (95% CI 19% to 42%) for individuals in the lowest quartile (<50.0 µg/L). In an age- and sex-adjusted analysis, the hazard ratio (HR) for death from all causes was 7.01 (95% CI 3.81 to 12.9) for patients in the lowest quartile of serum selenium, compared to those in the highest quartile. The corresponding multivariate HR was 3.07 (95% CI 1.59 to 5.94). CONCLUSIONS: This study suggests that a selenium level in excess of 70 µg/L is associated with improved outcome among patients undergoing treatment for laryngeal cancer. Further studies are needed to evaluate if selenium supplementation to achieve this level might improve overall prognosis.

Serum folate concentration and the incidence of lung cancer.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality globally. Folate helps to maintain DNA integrity and to regulate gene expression. Serum folate levels may affect the risk of several cancers, including lung cancer. In this study we evaluated the association between serum folate concentration and variations in genes involved in folate metabolism with lung cancer incidence in Poland. METHODS: The study included 366 lung cancer patients and 366 control subjects. We measured serum folate concentration and genotyped six variants in MTHFR, MTR and MTRR genes. The odds ratios of being diagnosed with lung cancer were calculated using conditional univariable and multivariable logistic regression with respect to folate level and genotypes. RESULTS: The mean serum folate level was lower in lung cancer cases than in control group (20.07 nmol/l vs. 22.52 nmol/l, p = 0.002). The odds ratio for lung cancer declined with increasing serum content of the folate. The folate concentration of >25.71 nmol/l (IVth quartile) in comparison to <15.92 nmol/l (Ist quartile) was associated with an odds ratio of 0.61 (95%CI 0.40-0.95, p = 0.03). The analysis of variations in MTHFR, MTR and MTRR genes did not reveal any significant difference between lung cancer cases and controls in univariable and multivariable analyses. CONCLUSION: In this case-control study, lower serum folate concentrations were associated with a higher risk of lung cancer diagnosis. Although previous findings have been somewhat mixed, our results add to the evidence that circulating folate levels may be an indicator of lung cancer risk.

Serum 25(OH)D concentration, common variants of the VDR gene and lung cancer occurrence.

The first aim of our study was to examine the association between common variants in VDR [rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI) and rs11568820 (Cdx2)] and lung cancer risk in the Polish population. Genotyping and statistical analysis which included Chi-square test with Yates correction and haplotype frequency analysis were performed on a series of 840 consecutively collected lung cancer patients and 920 healthy controls. The second aim was to evaluate the link between serum 25(OH)D concentration and the number of lung cancers in a subgroup of 200 patients. A separate control group that consisted of 400 matched (by age, sex, smoking habits and the season of blood collection) healthy individuals was used to avoid posterior adjustment on the matched variables. Statistical analysis with the use of Chi-square test with Yates was performed. We found no statistically significant difference in the distribution of the allels of studied VDR variants among cases and controls. A statistically significant over-representation of VDR haplotypes: rs731236_A + rs1544410_T [odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.11-5.32, p < 0.001], rs731236_G + rs1544410_T (OR = 1.54, 95% CI = 1.31-1.81, p < 0.001) and rs731236_G + rs1544410_C (OR = 0.04, 95% CI = 0.03-0.07, p < 0.001) was detected. We found a tendency toward an increased number of lung cancers among individuals with low serum levels of 25(OH)D. To answer the question, whether VDR can be regarded as lung cancer susceptibility gene and low 25(OH)D serum levels is associated with lung cancer occurrences, additional, multicenter study needs to be performed.

Serum Concentrations of Selenium and Copper in Patients Diagnosed with Pancreatic Cancer.

PURPOSE: Understanding of the etiology and pathogenesis of pancreatic cancer (PaCa) is still insufficient. This study evaluated the associations between concentrations of selenium (Se) and copper (Cu) in the serum of PaCa patients. MATERIALS AND METHODS: The study included 100 PaCa patients and 100 control subjects from the same geographical region in Poland. To determine the average concentration of Se, Cu, and ratio Cu:Se in the Polish population, assay for Se and Cu was performed in 480 healthy individuals. Serum levels of Se and Cu were measured using inductively coupled plasma mass spectrometry. RESULTS: In the control group, the average Se level was 76 µg/L and Cu 1,098 µg/L. The average Se level among PaCa patients was 60 µg/L and the mean Cu level was 1,432 µg/L. The threshold point at which any decrease in Se concentration was associated with PaCa was 67.45 µg/L. The threshold point of Cu level above which there was an increase in the prevalence of PaCa was 1,214.58 µg/L. In addition, a positive relationship was observed between increasing survival time and Se plasma level. CONCLUSION: This retrospective study suggests that low levels of Se and high levels of Cu might influence development of PaCa and that higher levels of Se are associated with longer survival in patients with PaCa. The results suggest that determining the level of Se and Cu could be incorporated into a risk stratification scheme for the selection and surveillance control examination to complement existing screening and diagnostic procedures.

Selenium as a marker of cancer risk and of selection for control examinations in surveillance.

Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinations in surveillance and as a marker of patients with high risk of cancers.

Can selenium levels act as a marker of colorectal cancer risk?

BACKGROUND: Selenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk. METHODS: A total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher's exact test. RESULTS: The threshold point of selenium level was 55 µg/l and 65 µg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer. CONCLUSIONS: The result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations.

A low selenium level is associated with lung and laryngeal cancers.

PURPOSE: It has been suggested that selenium deficiency is a risk factor for several cancer types. We conducted a case-control study in Szczecin, a region of northwestern Poland, on 95 cases of lung cancer, 113 cases of laryngeal cancer and corresponding healthy controls. METHODS: We measured the serum level of selenium and established genotypes for four variants in four selenoprotein genes (GPX1, GPX4, TXNRD2 and SEP15). Selenium levels in the cases were measured after diagnosis but before treatment. We calculated the odds of being diagnosed with lung or laryngeal cancer, conditional on selenium level and genotype. RESULTS: Among lung cancer cases, the mean selenium level was 63.2 µg/l, compared to a mean level of 74.6 µg/l for their matched controls (p<0.0001). Among laryngeal cancer cases, the mean selenium level was 64.8 µg/l, compared to a mean level of 77.1 µg/l for their matched controls (p<0.0001). Compared to a serum selenium value below 60 µg/l, a selenium level above 80 µg/l was associated with an odds ratio of 0.10 (95% CI 0.03 to 0.34; p = 0.0002) for lung cancer and 0.23 (95% CI 0. 09 to 0.56; p = 0.001) for laryngeal cancer. In analysis of four selenoprotein genes we found a modest evidence of association of genetic variant in GPX1 with the risk of lung and laryngeal cancers. CONCLUSION: A selenium level below 60 µg/l is associated with a high risk of both lung and laryngeal cancer.

Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study.

PURPOSE: Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland. METHODS: We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients. RESULTS: Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91). CONCLUSIONS: This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.