Zinc and Its Antioxidant Properties: The Potential Use of Blood Zinc Levels as a Marker of Cancer Risk in BRCA1 Mutation Carriers.

BRCA1 mutations predispose women to breast and ovarian cancer. The anticancer effect of zinc is typically linked to its antioxidant abilities and protecting cells against oxidative stress. Zinc regulates key processes in cancer development, including DNA repair, gene expression, and apoptosis. We took a blood sample from 989 female BRCA1 mutation carriers who were initially unaffected by cancer and followed them for a mean of 7.5 years thereafter. There were 172 incident cases of cancer, including 121 cases of breast cancer, 29 cases of ovarian cancers, and 22 cancers at other sites. A zinc level in the lowest tertile was associated with a modestly higher risk of ovarian cancer compared to women with zinc levels in the upper two tertiles (HR = 1.65; 95% CI 0.80 to 3.44; p = 0.18), but this was not significant. Among those women with zinc levels in the lowest tertile, the 10-year cumulative risk of ovarian cancer was 6.1%. Among those in the top two tertiles of zinc level, the ten-year cumulative risk of ovarian cancer was 4.7%. There was no significant association between zinc level and breast cancer risk. Our preliminary study does not support an association between serum zinc level and cancer risk in BRCA1 mutation carriers.

Blood Lead Level as Marker of Increased Risk of Ovarian Cancer in BRCA1 Carriers.

BRCA1 mutations substantially elevate the risks of breast and ovarian cancer. Various modifiers, including environmental factors, can influence cancer risk. Lead, a known carcinogen, has been associated with various cancers, but its impact on BRCA1 carriers remains unexplored. A cohort of 989 BRCA1 mutation carriers underwent genetic testing at the Pomeranian Medical University, Poland. Blood lead levels were measured using inductively coupled plasma mass spectrometry. Each subject was assigned to a category based on their tertile of blood lead. Cox regression analysis was used to assess cancer risk associations. Elevated blood lead levels (>13.6 µg/L) were associated with an increased risk of ovarian cancer (univariable: HR = 3.33; 95% CI: 1.23-9.00; p = 0.02; multivariable: HR = 2.10; 95% CI: 0.73-6.01; p = 0.17). No significant correlation was found with breast cancer risk. High blood lead levels are associated with increased risk of ovarian cancer in BRCA1 carriers, suggesting priority for preventive salpingo-oophorectomy. Potential risk reduction strategies include detoxification. Validation in diverse populations and exploration of detoxification methods for lowering lead levels are required.

Serum Levels of Copper and Zinc and Survival in Breast Cancer Patients.

There is emerging interest in the relationship between several serum micronutrients and the prognosis of patients with breast cancer. The relationship between serum zinc and copper levels and breast cancer prognosis is unclear. In our study, we included 583 patients with breast cancer diagnosed between 2008 and 2015 in the region of Szczecin, Poland. In a blood sample obtained before treatment, serum zinc and copper levels were quantified by mass spectroscopy. Each patient was assigned to one of four categories (quartiles) based on the distribution of the elements in the entire cohort. Patients were followed from diagnosis to death over a mean of 10.0 years. The 10-year overall survival was 58.3% for women in the highest and 82.1% for those in the lowest quartile of serum copper/zinc ratio (p < 0.001). The multivariate hazard ratio (HR) for breast cancer death was 2.07 (95% CI 1.17-3.63; p = 0.01) for patients in the highest quartile of serum copper/zinc ratio compared to those in the lowest. There is evidence that the serum zinc level and copper/zinc ratio provide an independent predictive value for overall survival and breast cancer-specific survival after breast cancer diagnosis.

Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients.

The most prevalent type of cancer among males is prostate cancer. Survival is considered quite good, but it can be further improved when risk factors are optimized. One of these factors is micronutrients, including Se and Zn. To our knowledge, the interaction between Se and Zn and prostate cancer remains undescribed. This study aimed to investigate the optimal levels of selenium (Se) and zinc (Zn) and their impact on the survival of individuals diagnosed with prostate cancer. A total of 338 prostate cancer patients were enrolled in this study, which was conducted in Poland between 2009 and 2015. Mass spectrometry, which uses inductively coupled plasma mass, was used to assess serum element levels before treatment. The study participants were categorized into quartiles (QI-QIV) based on the distributions of Se and Zn levels observed among surviving participants. Cox regression was used to assess the association between serum Se and Zn levels and the survival of prostate cancer patients. Our results reveal the effect of combined Se and Zn levels on survival in prostate cancer patients (SeQI-ZnQI vs. SeQIV-ZnQIV; HR = 20.9). These results need further research to establish Se/Zn norms for different populations.

Serum Essential Elements and Survival after Cancer Diagnosis.

In a prospective study, we measured the associations between three serum elements (Se, Zn and Cu) and the prognosis of 1475 patients with four different types of cancer (breast, prostate, lung and larynx) from University Hospitals in Szczecin, Poland. The elements were measured in serum taken after diagnosis and prior to treatment. Patients were followed from the date of diagnosis until death from any cause or until the last follow-up date (mean years of follow-up: 6.0-9.8 years, according to site). Kaplan-Meier curves were constructed for all cancers combined and for each cancer separately. Age-adjusted hazard ratios (HRs) were estimated using Cox regression. The outcome was all-cause mortality. A Se level in the highest quartile was also associated with a reduced mortality (HR = 0.66; 95%CI 0.49-0.88; p = 0.005) in all-cause mortality for all cancers combined. Zn level in the highest quartile was also associated with reduced mortality (HR = 0.55; 95%CI 0.41-0.75; p = 0.0001). In contrast, a Cu level in the highest quartile was associated with an increase in mortality (HR = 1.91; 95%CI 1.56-2.08; p = 0.0001). Three serum elements-selenium, zinc and copper-are associated with the prognosis of different types of cancer.

Blood Copper Levels and the Occurrence of Colorectal Cancer in Poland.

There is a need for sensitive and specific biomarkers for the early detection of colorectal cancer. In this retrospective study, we assessed whether a high blood copper level was associated with the presence of colorectal cancer. The blood copper level was measured among 187 colorectal cancer patients and 187 matched controls. Cases and controls were matched for sex, smoking status (yes/no) and year of birth. Among the cases, the mean blood copper level was 1031 µg/L (range 657 µg/L to 2043 µg/L) and among the controls, the mean blood copper level was 864 µg/L (range 589 µg/L to 1433 µg/L). The odds ratio for colorectal cancer for those in the highest quartile of copper level (versus the lowest) was 12.7 (95% CI: 4.98-32.3; p < 0.001). Of the patients with stage I-II colon cancer, 62% had a copper level in the highest quartile. A blood copper level in excess of 930 µg/L is associated with an increase in the prevalence of colorectal cancer in the Polish population and its potential use in early detection programs should be considered.

Low Blood-As Levels and Selected Genotypes Appears to Be Promising Biomarkers for Occurrence of Colorectal Cancer in Women.

In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used as a marker for the detection of colorectal cancer (CRC) among Polish women. A retrospective case-control study of CRC included 83 CRC cases and 78 healthy controls. From each study participant pre-treatment peripheral blood was collected for As level measurement by inductively coupled-plasma mass spectrometry (ICP-MS). We estimated the odds ratio (OR) of the association between blood-As levels and CRC using multivariable unconditional logistic regression models. A low blood-As level (0.27-0.67 µg/L) was associated with an increased frequency of CRC (OR: 3.69; p = 0.005). This correlation was significantly greater when participants carried particular gene variants: CAT, rs1001179-nonCC (OR: 19.4; p = 0.001); ABCB1 rs2032582-CC (OR: 14.8; p = 0.024); GPX1 rs1050450-CC (OR: 11.6; p = 0.002) and CRTC3 rs12915189-nonGG (OR: 10.3; p = 0.003). Our study provides strong evidence that low blood-As levels are significantly associated with increased CRC occurrence and that particular gene variants significantly enhanced this correlation however, due to the novelty of these findings, we suggest further validation before a definitive statement that the combined effect of low blood-As levels with specific gene polymorphisms is a suitable CRC biomarker.

Influence of the Levels of Arsenic, Cadmium, Mercury and Lead on Overall Survival in Lung Cancer.

The effects of heavy metals on cancer risk have been widely studied in recent decades, but there is limited data on the effects of these elements on cancer survival. In this research, we examined whether blood concentrations of the heavy metals arsenic, cadmium, mercury and lead were associated with the overall survival of lung cancer patients. The study group consisted of 336 patients with lung cancer who were prospectively observed. Blood concentrations of heavy metals were measured to study the relationship between their levels and overall survival using Cox proportional hazards analysis. The hazard ratio of death from all causes was 0.99 (p = 0.94) for arsenic, 1.37 (p = 0.15) for cadmium, 1.55 (p = 0.04) for mercury, and 1.18 (p = 0.47) for lead in patients from the lowest concentration quartile, compared with those in the highest quartile. Among the patients with stage IA disease, this relationship was statistically significant (HR = 7.36; p < 0.01) for cadmium levels in the highest quartile (>1.97-7.77 µg/L) compared to quartile I (0.23-0.57 µg/L, reference). This study revealed that low blood cadmium levels <1.47 µg/L are probably associated with improved overall survival in treated patients with stage IA disease.

Blood Arsenic Levels as a Marker of Breast Cancer Risk among BRCA1 Carriers.

An important group of breast cancers is those associated with inherited susceptibility. In women, several predisposing mutations in genes involved in DNA repair have been discovered. Women with a germline pathogenic variant in BRCA1 have a lifetime cancer risk of 70%. As part of a larger prospective study on heavy metals, our aim was to investigate if blood arsenic levels are associated with breast cancer risk among women with inherited BRCA1 mutations. A total of 1084 participants with pathogenic variants in BRCA1 were enrolled in this study. Subjects were followed from 2011 to 2020 (mean follow-up time: 3.75 years). During that time, 90 cancers were diagnosed, including 67 breast and 10 ovarian cancers. The group was stratified into two categories (lower and higher blood As levels), divided at the median (<0.85 µg/L and ≥0.85 µg/L) As level among all unaffected participants. Cox proportional hazards models were used to model the association between As levels and cancer incidence. A high blood As level (≥0.85 µg/L) was associated with a significantly increased risk of developing breast cancer (HR = 2.05; 95%CI: 1.18-3.56; p = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09-2.74; p = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in BRCA1.

Blood cadmium levels as a marker for early lung cancer detection.

BACKGROUND: We assessed whether blood cadmium levels were associated with incident lung cancer and could be used in the context of a screening program for early-stage lung cancer. MATERIAL AND METHODS: We measured blood cadmium levels among 205 lung cancer patients and 205 matched controls. Cases and controls were matched for sex, age and smoking history (total pack-years, years since cessation for former smokers). RESULTS: The odds ratio for those in the highest quartile of cadmium level (versus lowest) was four-fold (OR = 4.41, 95 % CI:2.01-9.67, p < 0.01). The association was present in former smokers (OR = 16.8, 95 % CI:3.96-71.2, p < 0.01), but not in current smokers (OR = 1.23, 95 % CI: 0.34-4.38) or in never smokers (OR not defined). Among former smokers, the association was present in both early- and late-stage lung cancer. CONCLUSION: Blood cadmium levels may be a marker to help with the early detection of lung cancer among former smokers.

Lung Cancer Occurrence-Correlation with Serum Chromium Levels and Genotypes.

Lung cancer is the leading cause of cancer-related death worldwide. Exposure to environmental and occupational carcinogens is an important cause of lung cancer. One of these substances is chromium, which is found ubiquitously across the planet. The International Agency for Research on Cancer has classified chromium(VI) as a human carcinogen. The aim of this study was to assess whether serum chromium levels, as well as DNA variants in selected genes involved in carcinogenesis, xenobiotic-metabolism, and oxidative stress could be helpful in the detection of lung cancer. We conducted a study using 218 lung cancer patients and 218 matched healthy controls. We measured serum chromium levels and genotyped ten genetic variants in ERCC2, XRCC1, MT1B, GSTP1, ABCB1, NQ01, CRTC3, GPX1, SOD2 and CAT. The odds ratios of being diagnosed with lung cancer were calculated using conditional logistic regression with respect to serum chromium level and genotypes. The odds ratio for the occurrence of lung cancer increased with increasing serum chromium levels. The difference between the quartiles with the lowest vs. highest chromium level was more than fourfold in the entire group (OR 4.52, CI 2.17-9.42, p < 0.01). This correlation was significantly increased by more than twice when specific genotypes were taken into consideration (ERCC-rs12181 TT, OR 12.34, CI 1.17-130.01, p = 0.04; CRTC3-rs12915189 non GG, OR 9.73, CI 1.58-60.10, p = 0.01; GSTP1-rs1695 non AA, OR 9.47, CI 2.06-43.49, p = < 0.01; CAT-rs1001179 non CC, OR 9.18, CI 1.64-51.24, p = 0.01). Total serum chromium levels > 0.1 µg/L were correlated with 73% (52/71) of lung cancers diagnosed with stage I disease. Our findings support the role of chromium and the influence of key proteins on lung cancer burden in the general population.

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.

Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland.

PURPOSE: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing (WES). MATERIALS AND METHODS: Herein we performed WES on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2Avariants. A replication study using a set of 1,200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken. RESULTS: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR1, NUDT17, and RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls. CONCLUSION: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5, and STK33 with melanoma risk.

BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population.

The association of BRCA1/2 mutations with melanoma is not completely determined; the interpretation of variants of unknown significance is also problematic. To evaluate these issues we explored the molecular basis of melanoma risk by performing whole-exome sequencing on a cohort of 96 unrelated Polish early-onset melanoma patients and targeted sequencing of BRCA1/2 genes on additional 30 melanoma patients with familial aggregation of breast and other cancers. Sequencing was performed on peripheral blood. We evaluated MutationTaster, Polyphen2, SIFT, PROVEAN algorithms, analyzed segregation with cancer disease (in both families with identified BRCA2 variants) and in one family performed LOH (based on 2 primary tumors). We found neither pathogenic mutations nor variants of unknown significance within BRCA1. We identified two BRCA2 variants of unknown significance: c.9334G>A and c.4534 C>T. Disease allele frequency was evaluated by genotyping of 1230 consecutive melanoma cases, 5000 breast cancer patients, 3500 prostate cancers and 9900 controls. Both variants were found to be absent among unselected cancer patients and healthy controls. The MutationTaster, Polyphen2 and SIFT algorithms indicate that c.9334G>A is a damaging variant. Due to lack of tumour tissue LOH analysis could not be performed for this variant. The variant segregated with the disease. The c.4534 C>T variant did not segregate with disease, there was no LOH of the variant. The c.9334G>A variant, classified as a rare variant of unknown significance, on current evidence may predisposes to cancers of the breast, prostate and melanoma. Functional studies to describe how the DNA change affects the protein function and a large multi-center study to evaluate its penetrance are required.

The Prevalence of Founder Mutations among Individuals from Families with Familial Pancreatic Cancer Syndrome.

PURPOSE: Familial pancreatic cancer describes families with at least two first-degree relatives with pancreatic cancer that do not fulfil the criteria of other inherited tumor syndromes with increased risks of pancreatic cancer. Although much has been learned regarding the aggregation of pancreatic cancer in some families, the genetic basis for this familial aggregation is poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among individuals from families with diagnosed familial pancreatic cancer syndrome and assessed their possible association with the familial pancreatic cancer (FPC) risk in Poland. MATERIALS AND METHODS: In this study, 400 FPC individuals and 4,000 control subjects were genotyped for founder mutations in BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), NBS1 (657del5), and PALB2 (509_510delGA, 172_175delTTGT) genes. RESULTS: A statistically significant association was observed between the 172_175delTTGT mutation of the PALB2 gene and an increased risk of FPC syndrome (odds ratio [OR], 10.05; p=0.048). In addition, an increased risk of cancer was observed in the FPC family members with a BRCA1 mutation (OR, 6.72; p=0.006). Novel associations were found between the FPC family members with cancer and CHEK2 mutations (OR, 2.26; p=0.008) with a noticeable contribution of the missense variant, I157T of CHEK2 (OR, 2.17; p=0.026). CONCLUSION: The founder mutations in the genes, BRCA1, PALB2, and CHEK2, cause a small percentage of familial pancreatic cancer syndrome in the Polish population. Following confirmation in larger studies, these mutations can be added to the panel of genes to be tested in families with a diagnosis of FPC syndrome.

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.

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.

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.

Smoking related cancers and loci at chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish population.

Genetic factors associated with the risk of smoking related cancers have until recently remained elusive. Since the publication of a genome-wide association study (GWAS) on lung cancer new genetic loci have been identified that appear to be associated with disease risk. In this replication study we genotyped 14 single nucleotide polymorphisms (SNPs) located at the 5p12.3-p15.33, 6p21.3-p22.1, 6q23-q27 and 15q25.1 loci in 874 lung, 450 bladder, 418 laryngeal cancer cases and cancer-free controls, matched by year of birth and sex to the cases. Our results revealed that loci in the chromosome region 15q25.1 (rs16969968[A], rs8034191[G]) and 5p15 (rs402710[T]) are associated with lung cancer risk in the Polish population (smoking status adjusted OR = 1.45, 1.35, 0.77; p ≤ 0.0001, 0.0005, 0.002; 95%CI 1.23-1.72, 1.14-1.59, 0.66-0.91 respectively). None of the other regions analyzed herein were implicated in the risk of lung, bladder or laryngeal cancer. This study supports previous findings on lung cancer but fails to show association of SNPs located in 15q25.1 and 5p15 region with other smoking related cancers like bladder and laryngeal cancer.