Publications by authors named "Tomasz Huzarski"

160 Publications

Genetic predisposition to male breast cancer in Poland.

BMC Cancer 2021 Aug 30;21(1):975. Epub 2021 Aug 30.

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

Background: Breast cancer in men accounts for fewer than 1 % of all breast cancer cases diagnosed in men and women. Genes which predispose to male breast cancer include BRCA1 and BRCA2. The role of other genes is less clear. In Poland, 20 founder mutations in BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL are responsible for the majority of hereditary breast cancer cases in women, but the utility this genes panel has not been tested in men.

Methods: We estimated the prevalence of 20 alleles in six genes (BRCA1, BRCA2, CHEK2, PALB2, NBN, RECQL) in 165 Polish male breast cancer patients. We compared the frequency of selected variants in male breast cancer cases and controls.

Results: One of the 20 mutations was seen in 22 of 165 cases (13.3%). Only one BRCA1 mutation and two BRCA2 mutations were found. We observed statistically significant associations for PALB2 and CHEK2 truncating mutations. A PALB2 mutation was detected in four cases (OR = 11.66; p < 0.001). A CHEK2 truncating mutation was detected in five cases (OR = 2.93;p = 0.02).

Conclusion: In conclusion, we recommend that a molecular test for BRCA1, BRCA2, PALB2 and CHEK2 recurrent mutations should be offered to male breast cancer patients in Poland.
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http://dx.doi.org/10.1186/s12885-021-08718-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406897PMC
August 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

Weight Gain and the Risk of Ovarian Cancer in and Mutation Carriers.

Cancer Epidemiol Biomarkers Prev 2021 Aug 23. Epub 2021 Aug 23.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among and mutation carriers.

Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.

Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; = 0.02). Current BMI of 26.5 kg/m or greater was associated with an increased risk of ovarian cancer in mutation carriers, compared with those with a BMI less than 20.8 kg/m (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.

Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a or mutation.

Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0296DOI Listing
August 2021

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

HGG Adv 2021 Jul 16;2(3). Epub 2021 Jun 16.

Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
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http://dx.doi.org/10.1016/j.xhgg.2021.100042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312632PMC
July 2021

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy.

Eur J Cancer 2021 Sep 19;154:190-200. Epub 2021 Jul 19.

National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia; Department of Medical Oncology, St George Hospital, Kogarah, NSW 2217, Australia; Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia.

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients.

Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib.

Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot).

Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.
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http://dx.doi.org/10.1016/j.ejca.2021.06.024DOI Listing
September 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

Adjuvant Olaparib for Patients with - or -Mutated Breast Cancer.

N Engl J Med 2021 06 3;384(25):2394-2405. Epub 2021 Jun 3.

From the Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research (A.N.J.T.), and the Breast Cancer Now Unit, Guy's Hospital Cancer Centre, King's College London (A.N.J.T.), London, AstraZeneca, Cambridge (S.J.H., N.B.), and Frontier Science (Scotland), Kincraig (R.M.C., E.M.F., C.C.) - all in the United Kingdom; Dana-Farber Cancer Institute, Harvard Medical School (J.E.G., R.D.G.), Frontier Science Foundation (R.D.G.), and Harvard T.H. Chan School of Public Health (R.D.G.) - all in Boston; the Breast Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (B.K.); the University of Milan, European Institute of Oncology IRCCS, Milan (G.V.); Breast International Group (D.F., A.A.) and Institut Jules Bordet, l'Université Libre de Bruxelles (E.A., M.P.), Brussels; NRG Oncology (P.R., H.B., P.C.L., N.W., G.Y., C.E.G.) and the Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania (S.M.D.), Philadelphia, and the UPMC Hillman Cancer Center (P.R., P.C.L., N.W.) and the Department of Biostatistics (H.B., J.P.C., G.Y.), University of Pittsburgh, and the NSABP Foundation (N.W.), Pittsburgh - all in Pennsylvania; AstraZeneca, Gaithersburg (A.F.), and the National Cancer Institute, Rockville (L.A.K.) - both in Maryland; Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital (J.B.) - both in Barcelona; BC Cancer, Vancouver, BC, Canada (K.A.G.); Sahlgrenska University Hospital (B.L.) and the Institute of Clinical Sciences, Department of Oncology, Sahlgrenska Academy, Gothenburg University (B.L.) - both in Gothenburg, Sweden; the Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk (E.S.), the Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw (Z.N.), the International Hereditary Cancer Center, Pomeranian Medical University, Szczecin (T.H.), and Read-Gene, Grzepnica (T.H.) - all in Poland; Kaiser Permanente Vallejo Medical Center, Vallejo (J.M.S.), and the UCLA Fielding School of Public Health, David Geffen School of Medicine at UCLA (P.A.G.), and the UCLA Jonsson Comprehensive Cancer Center (P.A.G.), Los Angeles - all in California; Fudan University Shanghai Cancer Center, Shanghai, China, (Z.S.); Georgia NCORP, Northside Hospital Cancer Institute (A.W.P.), and Piedmont Healthcare (A.W.P.) - both in Atlanta; German Breast Group, Neu-Isenburg (S.L.), the Center for Hematology and Oncology Bethanien and Goethe University, Frankfurt (S.L.), and the Center for Familial Breast and Ovarian Cancer and the Center for Integrated Oncology, Faculty of Medicine, University Hospital Cologne, Cologne (R.S.) - all in Germany; the Department of Internal Medicine I and Gaston H. Glock Research Center, Medical University of Vienna, Vienna (G.G.S.); Merck, Kenilworth, NJ (V.K.); the University of Queensland Centre for Clinical Research and Pathology Queensland (S.R.L.) - both in Brisbane, QLD, Australia; and Houston Methodist Cancer Center (C.E.G.) and Weill Cornell Medical College (C.E.G.) - both in Houston.

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with or germline mutation-associated early breast cancer.

Methods: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with or germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.

Results: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.

Conclusions: Among patients with high-risk, HER2-negative early breast cancer and germline or pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
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http://dx.doi.org/10.1056/NEJMoa2105215DOI Listing
June 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

Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 05 18;22(5):620-631. Epub 2021 Mar 18.

Association de Recherche Contre les Cancers dont Gynécologiques-ARCAGY, Paris, France.

Background: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival.

Methods: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients.

Findings: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]).

Interpretation: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.

Funding: AstraZeneca and Merck.
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http://dx.doi.org/10.1016/S1470-2045(21)00073-5DOI Listing
May 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

Survival from breast cancer in women with a BRCA2 mutation by treatment.

Br J Cancer 2021 04 18;124(9):1524-1532. Epub 2021 Feb 18.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.

Background: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation.

Methods: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features.

Results: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56).

Conclusions: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
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http://dx.doi.org/10.1038/s41416-020-01164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076275PMC
April 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy.

Eur J Cancer 2020 11 23;139:59-67. Epub 2020 Sep 23.

Université Paris Descartes, Paris, France; ARCAGY-GINECO, France.

Background: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo.

Methods: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV).

Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST.

Conclusions: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
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http://dx.doi.org/10.1016/j.ejca.2020.08.021DOI 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

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

A comparison of ovarian cancer mortality in women with BRCA1 mutations undergoing annual ultrasound screening or preventive oophorectomy.

Gynecol Oncol 2019 11 26;155(2):270-274. Epub 2019 Sep 26.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Electronic address:

Objective: To compare the survival experience of women with a BRCA1 mutation who enrolled in an ovarian cancer screening program with that of women who opted for preventive oophorectomy.

Methods: We followed 1964 women with a BRCA1 mutation and two ovaries intact in a prospective study. No women had ovarian cancer or had a bilateral oophorectomy prior to study initiation. There were 1814 women in the cohort who had at least one screening ultrasound. They were followed from the date of first ultrasound until the date of preventive oophorectomy, death or last follow-up. There were 659 women in the cohort who had preventive oophorectomy. They were followed from the date of preventive oophorectomy until death or last follow-up.

Results: Among the 1196 women who had one or more ultrasound examinations and no oophorectomy, there were 73 incident cancers detected and 27 deaths from ovarian/fallopian cancer. The ten year cumulative risk of death was 2.0%. Among the 659 women who had a preventive oophorectomy there were 12 incident cancers (9 detected at oophorectomy and 3 in the follow up period) and two deaths from ovarian cancer. The ten year cumulative risk of death was 0.5%. The hazard ratio for oophorectomy versus ultrasound was 0.23 (95% CI: 0.05 to 0.97; p = 0.05).

Conclusion: The survival of women diagnosed with ovarian cancer enrolled in an ultrasound screening program is relatively poor and screening is not a viable alternative to preventive oophorectomy.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.034DOI Listing
November 2019

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

Int J Cancer 2020 03 29;146(5):1293-1298. Epub 2019 Sep 29.

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

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.
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http://dx.doi.org/10.1002/ijc.32655DOI Listing
March 2020

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

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

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018
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