Publications by authors named "Tadeusz Debniak"

120 Publications

Survival of bladder or renal cancer in patients with CHEK2 mutations.

PLoS One 2021 9;16(9):e0257132. Epub 2021 Sep 9.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

Purpose: The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer.

Materials And Methods: 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (≤60; >61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive).

Results: We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02-1.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50-42.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30-4.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02-0.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07-0.76; p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19-3.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12-0.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95-67.7; p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% (p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% (p = 0.5).

Conclusion: CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257132PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428549PMC
September 2021

Serum Selenium Level and 10-Year Survival after Melanoma.

Biomedicines 2021 Aug 11;9(8). Epub 2021 Aug 11.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland.

Melanoma is one of the most aggressive human malignancies. The determination of prognostic biomarkers is important for the early detection of recurrence and for the enrollment of the patients into different treatment regimens. Herein, we report the 10-year survival of 375 melanoma patients depending on their serum selenium levels. The study group was followed up from the date of melanoma diagnosis until death or 2020. Patients were assigned to one of four categories, in accordance with the increasing selenium level (I-IV quartiles). The subgroup with low selenium levels had a significant lower survival rate in relation to patients with high selenium levels, HR = 8.42; = 0.005 and HR = 5.83; = 0.02, for uni- and multivariable models, respectively. In the univariable analysis, we also confirmed the association between Breslow thickness, Clark classification and age at melanoma prognosis. In conclusion, a low serum selenium level was associated with an increased mortality rate in the 10 years following melanoma diagnosis. Future studies in other geographic regions with low soil selenium levels should be conducted to confirm our findings.
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http://dx.doi.org/10.3390/biomedicines9080991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392027PMC
August 2021

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

Biomolecules 2021 08 5;11(8). Epub 2021 Aug 5.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland.

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 ( = 0.94) for arsenic, 1.37 ( = 0.15) for cadmium, 1.55 ( = 0.04) for mercury, and 1.18 ( = 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; < 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.
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http://dx.doi.org/10.3390/biom11081160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392714PMC
August 2021

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

Cancers (Basel) 2021 Jul 3;13(13). Epub 2021 Jul 3.

Department of Genetics and Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland.

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 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 mutations. A total of 1084 participants with pathogenic variants in 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; = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09-2.74; = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in .
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http://dx.doi.org/10.3390/cancers13133345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269342PMC
July 2021

PALB2 mutations and prostate cancer risk and survival.

Br J Cancer 2021 Aug 18;125(4):569-575. Epub 2021 May 18.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Background: The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers.

Methods: We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers.

Results: A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006).

Conclusion: In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.
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http://dx.doi.org/10.1038/s41416-021-01410-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368211PMC
August 2021

Serum Selenium Level Predicts 10-Year Survival after Breast Cancer.

Nutrients 2021 Mar 16;13(3). Epub 2021 Mar 16.

Read-Gene S.A., 72-003 Grzepnica, Poland.

In a recent prospective study, we reported an association between a low serum selenium level and five-year survival among breast cancer patients. We now have updated the cohort to include 10-year survival rates. A blood sample was obtained from 538 women diagnosed with first primary invasive breast cancer between 2008 and 2015 in the region of Szczecin, Poland. Blood was collected before initiation of treatment. Serum selenium levels were quantified by mass spectroscopy. Each patient was assigned to one of four quartiles based on the distribution of serum selenium levels in the whole cohort. Patients were followed from diagnosis until death or last known alive (mean follow-up 7.9 years). The 10-year actuarial cumulative survival was 65.1% for women in the lowest quartile of serum selenium, compared to 86.7% for women in the highest quartile ( < 0.001 for difference). Further studies are needed to confirm the protective effect of selenium on breast cancer survival. If confirmed this may lead to an investigation of selenium supplementation on survival of breast cancer patients.
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http://dx.doi.org/10.3390/nu13030953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998294PMC
March 2021

Recurrent Mutations in , , , and in Polish Patients with Ovarian Cancer.

Cancers (Basel) 2021 Feb 18;13(4). Epub 2021 Feb 18.

Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland.

The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in , , , , and genes with ovarian cancer risk among unselected patients in Poland. We genotyped 21 recurrent germline mutations in (9 mutations), (4 mutations), (3 mutations), (2 mutations), and (3 mutations) among 2270 Polish ovarian cancer patients and 1743 healthy controls, and assessed the odds ratios (OR) for developing ovarian cancer for each gene. Mutations were detected in 369 out of 2095 (17.6%) unselected ovarian cancer cases and 117 out of 1743 (6.7%) unaffected controls. The ovarian cancer risk was associated with mutations in (OR = 40.79, 95% CI: 18.67-114.78; = 0.29 × 10), in (OR = 25.98; 95% CI: 1.55-434.8; = 0.001), in (OR = 6.28; 95% CI 1.77-39.9; = 0.02), and in (OR 3.34; 95% CI: 1.06-14.68; = 0.06). There was no association found for We found that pathogenic mutations in , , or are responsible for 12.5% of unselected cases of ovarian cancer. We recommend that all women with ovarian cancer in Poland and first-degree female relatives should be tested for this panel of 18 mutations.
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http://dx.doi.org/10.3390/cancers13040849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921976PMC
February 2021

Recurrent PALB2 mutations and the risk of cancers of bladder or kidney in Polish population.

Hered Cancer Clin Pract 2021 Jan 8;19(1). Epub 2021 Jan 8.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252, Szczecin, Poland.

Introduction: The role of PALB2 in carcinogenesis remains to be clarified. Our main goal was to determine the prevalence of PALB2 (509_510delGA and 172_175delTTGT) mutations in bladder and kidney cancer patients from Polish population.

Materials And Methods: 1413 patients with bladder and 810 cases with kidney cancer and 4702 controls were genotyped for two PALB2 variants: 509_510delGA and 172_175delTTGT.

Results: Two mutations of PALB2 gene were detected in 5 of 1413 (0.35%) unselected bladder cases and in 10 of 4702 controls (odds ratio [OR], 1.7; 95% CI 0.56-4.88; p = 0.52). Among 810 unselected kidney cancer cases two PALB2 mutations were reported in two patients (0,24%) (odds ratio [OR], (OR = 1.2; 95% CI 0.25-5.13; p = 0.84). In cases with mutations in PALB2 gene cancer family history was negative.

Conclusion: We found no difference in the prevalence of recurrent PALB2 mutations between cases and healthy controls. The mutations in PALB2 gene seem not to play a major role in bladder and kidney cancer development in Polish patients.
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http://dx.doi.org/10.1186/s13053-020-00161-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796646PMC
January 2021

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

J Trace Elem Med Biol 2021 Mar 12;64:126682. Epub 2020 Nov 12.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra (Szczecińska), Poland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jtemb.2020.126682DOI Listing
March 2021

Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population.

Eur J Cancer Prev 2020 11;29(6):511-519

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Evaluation of the prevalence of POT1, ACD, and TERF2IP mutations among Polish melanoma patients. A cohort of 60 patients from melanoma-prone families, 1500 unselected cases and 1500 controls were genotyped. Methodology included Sanger sequencing, in-silico software predilection, and TaqMan assays. We identified three nonsynonymous variants: POT1 c.903 G>T; TERF2IP c.970 A>G; and ACD c.1544 T>C and a splice site variant ACD c.645 G>A. The c.903 G>T was predicted to be pathogenic according to PolyPhen-2, benign according to Mutation Taster, PROVEAN, AGVGD, and SIFT. The c.645 G>A was defined as disease caused by Mutation Taster and Human Splicing Finder and as variant of unknown significance by ClinVar. The other detected variants were described as benign. The c.903 G>T variant was present in two unselected cases and one control [P = 0.57, odds ratio (OR) = 2.00]; the c.645 G>A variant was not detected among the unselected cases and the controls; the c.970 A>G variant was present in 110 cases and 133 controls (P = 0.14, OR = 0.81); the c.1544 T>C variant was present in 687 cases and 642 controls (P = 0.11, OR = 1.07). We found no loss of heterozygosity of the c.903 G>T, c.970 A>G, and c.645 G>A variants. C.645 G>A variant had no effect on splicing or expression. The changes in POT1 c.903 G>T and ACD c.645 G>A can be classified as rare variants of unknown significance, the other variants appear to be polymorphisms. Germline mutations in POT1, ACD, and TERF2IP are infrequent among Polish melanoma patients.
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http://dx.doi.org/10.1097/CEJ.0000000000000633DOI Listing
November 2020

Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population.

Breast Cancer 2021 Jan 4;28(1):226-235. Epub 2020 Sep 4.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

Background: The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which has not been determined until now.

Methods: A cohort of 100 females with BC diagnosed ≤ 30 years of age and with a positive family history of cancer was used as a discovery cohort. 1880 women with BC ≤ 45 years old and a control group of 2000 healthy women were genotyped as a replication phase of this study.

Results: Four heterozygous pathogenic missense mutations were detected in a group of 100 patients with early-onset breast cancer. On the basis of software prediction and available literature data, all these variants were defined as pathogenic. None of these TP53 variants were detected among 1880 breast cancer patients and 2000 healthy controls. No large mutations were found among early-onset cases using MLPA reaction.

Conclusion: Germline pathogenic TP53 variants were found in 4% early-onset Polish BC patients. No founder mutations were identified in Polish population. To improve the treatment and surveillance screening, the search for germline TP53 pathogenic variants is recommended for all female BC cases diagnosed ≤ 30 years old.
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http://dx.doi.org/10.1007/s12282-020-01151-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796867PMC
January 2021

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.

Int J Cancer 2020 11 11;147(10):2793-2800. Epub 2020 Sep 11.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.
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http://dx.doi.org/10.1002/ijc.33272DOI Listing
November 2020

Prevalence of Recurrent Mutations Predisposing to Breast Cancer in Early-Onset Breast Cancer Patients from Poland.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland.

There are twenty recurrent mutations in six breast-cancer-predisposing genes in Poland (BRCA1, BRCA2, CHEK2, PALB2, NBN, and RECQL). The frequencies of the twenty alleles have not been measured in a large series of early-onset breast cancer patients from Poland unselected for family history. We genotyped 2464 women with breast cancer diagnosed below age 41 years for twenty recurrent germline mutations in six genes, including BRCA1, BRCA2 CHEK2, PALB2, NBN, and RECQL. A mutation in one of the six genes was identified in 419 of the 2464 early-onset breast cancer cases (17%), including 22.4% of those cases diagnosed below age 31. The mutation frequency was 18.8% for familial breast cancer cases and 6% for non-familial cases. Among women with breast cancer below age 31, the mutation frequency was 23.6% for familial cases and 17.4% in non-familial cases. The majority of mutations (76.2%) were seen in BRCA1 and BRCA2. In Poland, a panel of twenty recurrent mutations in six genes can identify a genetic basis for a high percentage of early-onset cases and testing is recommended for all women with breast cancer at age 40 or below.
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http://dx.doi.org/10.3390/cancers12082321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465341PMC
August 2020

Polymorphisms in , , and do not contribute to breast, lung and colon cancer risk in polish population.

Hered Cancer Clin Pract 2020 31;18:16. Epub 2020 Jul 31.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

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 rs243865 in rs11568818 in rs2252070 in and rs28366003 in 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 , and non-significant differences in genotypes frequencies among cases and controls were observed.

Conclusions: Analyses of polymorphisms, rs1799750 in , rs243865 in , rs11568818 in , rs2252070 in and rs28366003 in 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.
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http://dx.doi.org/10.1186/s13053-020-00147-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395404PMC
July 2020

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

Biol Trace Elem Res 2021 Apr 9;199(4):1228-1236. Epub 2020 Jul 9.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland.

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.
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http://dx.doi.org/10.1007/s12011-020-02240-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886837PMC
April 2021

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

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

Hered Cancer Clin Pract 2019 23;17:33. Epub 2019 Dec 23.

3Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

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 ( = 97) and controls ( = 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;  = 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;  = 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.
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http://dx.doi.org/10.1186/s13053-019-0131-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929308PMC
December 2019

Inherited Variants in and the Risk and Clinical Characteristics of Breast Cancer.

Cancers (Basel) 2019 Oct 13;11(10). Epub 2019 Oct 13.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland.

Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the gene. To investigate whether heterozygous carriers of a mutation are predisposed to breast cancer, we sequenced in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6-1.6). Clinical characteristics of breast cancers in the mutation carriers and non-carriers were similar. Loss of the wild-type allele was not detected in cancers from the mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of as an autosomal dominant breast cancer susceptibility gene.
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http://dx.doi.org/10.3390/cancers11101548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826355PMC
October 2019

Inherited variants in XRCC2 and the risk of breast cancer.

Breast Cancer Res Treat 2019 Dec 28;178(3):657-663. Epub 2019 Aug 28.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252, Szczecin, Poland.

Background: XRCC2 participates in homologous recombination and in DNA repair. XRCC2 has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer susceptibility gene panels.

Methods: We sequenced XRCC2 in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the XRCC2 founder mutation.

Results: We identified a recurrent truncating mutation of XRCC2 (c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48-1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27-2.65). Breast cancers in XRCC2 mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type XRCC2 allele was observed only in one of the eight breast cancers from patients who carried the XRCC2 mutation. No cancer type was more common in first- or second-degree relatives of XRCC2 mutation carriers than in relatives of the non-carriers.

Conclusion: XRCC2 c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider XRCC2 as a breast cancer-predisposing gene.
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http://dx.doi.org/10.1007/s10549-019-05415-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817746PMC
December 2019

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

J Trace Elem Med Biol 2019 Dec 26;56:46-51. Epub 2019 Jul 26.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jtemb.2019.07.010DOI Listing
December 2019

Allelic modification of breast cancer risk in women with an NBN mutation.

Breast Cancer Res Treat 2019 Nov 13;178(2):427-431. Epub 2019 Aug 13.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252, Poland.

Background: NBN 657del5 founder mutation predisposes to breast and prostate cancer. Recently, it has been reported that the pathogenicity of this mutation with regard to prostate cancer risk is modified by a missense variant of the same gene (E185Q).

Methods: To evaluate the interaction of the 657del5 and E185Q founder alleles of NBN on breast cancer risk in Poland, 4964 women with breast cancer and 6152 controls were genotyped for these two recurrent variants of NBN (657del5 truncating variant and E185Q missense variant).

Results: The NBN 657del5 mutation was detected in 57 of 4964 unselected cases and in 35 of 6152 controls (OR = 2.0, p = 0.001). The E185Q GG genotype was detected in 2167 of 4964 unselected cases and in 2617 of 6152 controls (OR = 1.04, p = 0.3). In carriers of the 657del5 deletion, the elevated cancer risk was restricted to women with the GG genotype of the E185Q variant (OR = 3.6, 95% CI 1.9-6.6; p < 0.0001). Among women with other E185Q genotypes, the OR associated with 657del5 was 1.0 (95% CI 0.5-1.8; p = 0.9). The interaction between the two alleles was statistically significant (homogeneity p = 0.003).

Conclusion: In Poland, the pathogenicity of the NBN 657del5 mutation is restricted to women with a homozygous GG genotype of missense variant of the same gene (E185Q). This is the first clear example whereby a moderate penetrance breast cancer gene is impacted by a genetic modifier.
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http://dx.doi.org/10.1007/s10549-019-05391-wDOI Listing
November 2019

Blood arsenic levels and the risk of familial breast cancer in Poland.

Int J Cancer 2020 05 26;146(10):2721-2727. Epub 2019 Aug 26.

Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

Arsenic is recognized as a potent carcinogen at high concentrations, but the relationship between environmental arsenic and breast cancer risk has not well been studied. Most research has focused on the effect of arsenic in populations with high endemic exposure, and not in populations with arsenic levels within normal limits. We sought to determine if blood arsenic levels predict the risk of breast and other cancers risk among women in northern Poland. The cohort consisted of 1,702 healthy women, aged 40 and above, identified between 2010 and 2017. Blood arsenic level was determined by inductively coupled plasma mass spectrometry. After an average of 4.5 years of follow-up (range 0.7-7.3 years), there were 110 incident cases of cancer diagnosed in the cohort, including 68 cases of breast cancer. Women in the highest quartile of arsenic had a highly significant 13-fold increased risk of developing breast cancer, compared to women in the lowest quartile (hazard ratio [HR] = 13.2; 95% confidence interval [CI] 4.02-43.0). Results were similar for arsenic and all incident cancers (HR quartile 4 vs. quartile 1 = 13.3; 95% CI 4.78-37.0). If confirmed, our study suggests that the blood arsenic level may be a useful predictive marker of cancer risk in women.
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http://dx.doi.org/10.1002/ijc.32595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154768PMC
May 2020

The spectrum of mutations predisposing to familial breast cancer in Poland.

Int J Cancer 2019 12 26;145(12):3311-3320. Epub 2019 Jun 26.

Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada.

To optimize genetic testing, it is necessary to establish the spectrum of breast cancer-predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non-BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2-positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non-BRCA-positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.
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http://dx.doi.org/10.1002/ijc.32492DOI Listing
December 2019

is A Low/Moderate Breast Cancer Risk Gene: Evidence Based on An Association Study of the Central European p.Q564X Recurrent Mutation.

Cancers (Basel) 2019 May 28;11(6). Epub 2019 May 28.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61704 Poznan, Poland.

In addition to several well-established breast cancer (BC) susceptibility genes, the contribution of other candidate genes to BC risk remains mostly undefined. is a potentially predisposing BC gene, however, the rarity of its mutations and an insufficient family/study size have hampered corroboration and estimation of the associated cancer risks. To clarify the role of mutations in BC predisposition, a comprehensive case-control association study of a recurring nonsense mutation c.1690C>T (p.Q564X) was performed, comprising ~14,000 unselected BC patients and ~5900 controls from Polish and Belarusian populations. For comparisons, two variants of unknown significance were also genotyped. We detected the highest number of variants in BC cases in any individual -specific study, including 38 p.Q564X mutations. The p.Q564X was associated with a moderately increased risk of BC (OR = 2.30, = 0.04). The estimated risk was even higher for triple-negative BC and bilateral BC. As expected, the two tested variants of unknown significance did not show significant associations with BC risk. Our study provides substantial evidence for the association of a deleterious mutation with BC as a low/moderate risk allele. The p.Q564X was shown to be a Central European recurrent mutation with potential relevance for future genetic testing.
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http://dx.doi.org/10.3390/cancers11060740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627038PMC
May 2019

Age-specific risks of incident, contralateral and ipsilateral breast cancer among 1776 Polish BRCA1 mutation carriers.

Breast Cancer Res Treat 2019 Apr 5;174(3):769-774. Epub 2019 Jan 5.

Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada.

Purpose: Women with an inherited germline BRCA1 mutation have a high lifetime risk of developing breast cancer. We have previously shown that, among BRCA mutation carriers, incidence rates of breast cancer vary by country of residence.

Methods: In the current study, we prospectively calculated the cumulative and annual incidence rates of incident breast cancer, contralateral breast cancer and ipsilateral breast cancer recurrence among BRCA1 mutation carriers in Poland. Study subjects comprised a cohort of 1776 Polish women with a BRCA1 mutation who had no prior diagnosis of breast or ovarian cancer at the time of enrollment, the women were followed with a biennial follow-up by questionnaire. Women were followed for an average of 6.1 years (range 0.0-18.2) and 191 new breast cancer cases were diagnosed.

Results: The cumulative incidence of breast cancer to age 70 was 52%. The annual risk of breast cancer was estimated at 1.78%; the maximum annual risk was observed between the ages of 30 and 65. Among the 941 women with a prior diagnosis of breast cancer, 106 women developed a contralateral breast cancer. The 20-year cumulative incidence of contralateral breast cancer was 31% and the annual rate of contralateral breast cancer was 1.96%. There were 11 recurrences among the 215 women with breast cancer (ipsilateral breast cancers). The cumulative incidence at 20 years was 17% and the annual rate of an ipsilateral recurrence was 1.03%.

Conclusion: Our findings confirm the high annual rates of early-onset incident, contralateral and recurrent breast cancer among Polish BRCA1 mutation carriers. These risk estimates are important in the context of the clinical management of unaffected women as well as in the treatment of newly diagnosed primary breast cancers and can also be used as the basis for the planning of prevention trials.
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http://dx.doi.org/10.1007/s10549-018-05076-wDOI Listing
April 2019

Inherited NBN Mutations and Prostate Cancer Risk and Survival.

Cancer Res Treat 2019 Jul 13;51(3):1180-1187. Epub 2018 Dec 13.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

Purpose: To establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival.

Materials And Methods: Five thousand one hundred eighty-nine men with prostate cancer and 6,152 controls were genotyped for four recurrent variants of NBN (657del5, R215W, I171V, and E185Q).

Results: The NBN 657del5 mutation was detected in 74 of 5,189 unselected cases and in 35 of 6,152 controls (odds ratio [OR], 2.5; p < 0.001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95% confidence interval [CI], 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI, 0.8 to 2.4) and the interaction was significant (homogeneity p=0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (hazard ratio [HR], 1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR, 1.9; p=0.0004).

Conclusion: The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q).
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http://dx.doi.org/10.4143/crt.2018.532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639207PMC
July 2019

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

PLoS One 2018 4;13(10):e0204768. Epub 2018 Oct 4.

Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171837PMC
March 2019

Genetic polymorphisms may influence the vertical growth rate of melanoma.

J Cancer 2018 6;9(17):3078-3083. Epub 2018 Aug 6.

Department of Dermatology, Medical University of Warsaw, 02-008 Warsaw, Poland.

Identification of new predictive markers in melanoma is of great clinical importance. This study was aimed to analyze association between selected common variants in the cancer susceptibility genes and melanoma progression at the time of diagnosis. The study included 243 consecutive patients with melanoma. Genotyping was performed using real-time PCR. Our data revealed modest association between xeroderma pigmentosum complementation group D (XPD) codon 312 polymorphism and tumor thickness (as defined by Breslow score; XPD D312N CC: 3.00 ± 3.78mm, CT: 1.71 ± 2.48mm, TT: 2,53 ± 3,24mm, P=0.023). The CT genotype in XPD D312N polymorphism was more frequently represented in non-invasive melanomas compared to deeply penetrating tumors. None of the common SNPs in cyclin dependent kinase inhibitor 2A (CDKN2A), vitamin D receptor (VDR), melanocortin 1 receptor (MC1R) were associated with Breslow depth. These findings suggest that genetic alteration in XPD contributes to melanoma progression and may be a potential diagnostic and molecular prognostic marker.
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http://dx.doi.org/10.7150/jca.26404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134810PMC
August 2018

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

PLoS One 2018 23;13(7):e0201065. Epub 2018 Jul 23.

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056054PMC
January 2019

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.

Cancer Res Treat 2019 Jan 14;51(1):337-344. Epub 2018 May 14.

Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, 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.
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http://dx.doi.org/10.4143/crt.2018.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333986PMC
January 2019
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