Variants in ATRIP are associated with breast cancer susceptibility in the Polish population and UK Biobank.

Several breast cancer susceptibility genes have been discovered, but more are likely to exist. To identify additional breast cancer susceptibility genes, we used the founder population of Poland and performed whole-exome sequencing on 510 women with familial breast cancer and 308 control subjects. We identified a rare mutation in ATRIP (GenBank: NM_130384.3: c.1152_1155del [p.Gly385Ter]) in two women with breast cancer. At the validation phase, we found this variant in 42/16,085 unselected Polish breast cancer-affected individuals and in 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). By analyzing the sequence data of the UK Biobank study participants (450,000 individuals), we identified ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. We showed that tumors of women with breast cancer who have a germline ATRIP mutation have loss of heterozygosity at the site of ATRIP mutation and genomic homologous recombination deficiency. ATRIP is a critical partner of ATR that binds to RPA coating single-stranded DNA at sites of stalled DNA replication forks. Proper activation of ATR-ATRIP elicits a DNA damage checkpoint crucial in regulating cellular responses to DNA replication stress. Based on our observations, we conclude ATRIP is a breast cancer susceptibility gene candidate linking DNA replication stress to breast cancer.

Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis.

BACKGROUND: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. METHODS: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. RESULTS: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05-1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. CONCLUSIONS: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

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 BRCA1 or BRCA2 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 BRCA1 or BRCA2 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 BRCA1 or BRCA2 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.).

Incidence of endometrial cancer in BRCA mutation carriers.

OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

PURPOSE: Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. METHODS: We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. RESULTS: There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07). CONCLUSION: Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

Genetic testing for hereditary breast cancer in Poland: 1998-2022.

BRCA1 and BRCA2 mutations contribute to both breast cancer and ovarian cancer worldwide. In Poland approximately 4% of patients with breast cancers and 10% of patients with ovarian cancer carry a mutation in BRCA1. The majority of mutations consist of three founder mutations. A rapid inexpensive test for these three mutations can be used to screen all Polish adults at a reasonable cost. In the region of Pomerania of North-western Poland nearly half a million tests have been performed, in large part through engaging family doctors and providing ready access to testing through the Pomeranian Medical University. The following commentary provides a history of genetic testing for cancer in Pomerania and the current approach to facilitating access to genetic testing at the Cancer Family Clinic for all adults living in the region.

The impact of oophorectomy on survival from breast cancer in patients with CHEK2 mutations.

BACKGROUND: To estimate the impact of oophorectomy and other treatments on the survival of breast cancer patients with a CHEK2 mutation. METHODS: Women with Stage I-III breast cancer who were treated at 17 hospitals in Poland were tested for four founder mutations in the CHEK2 gene. 974 women (10%) were positive for a CHEK2 mutation. Control patients without a CHEK2 mutation were selected from a database of patients treated over the same time period. Information on treatments received and distant recurrences were retrieved from medical records. Treatments included chemotherapy, hormonal therapy (tamoxifen) and radiation therapy. Oophorectomies were performed for the treatment of breast cancer or for benign conditions. Dates of death were obtained from the Polish Vital Statistics Registry. Causes of death were determined by medical record review. Predictors of survival were determined using the Cox proportional hazards model. RESULTS: In all, 839 patients with a CHEK2 mutation were matched to 839 patients without a mutation. The mean follow-up was 12.0 years. The 15-year survival for CHEK2 carriers was 76.6% and the 15-year survival for non-carrier control patients was 78.8% (adjusted HR = 1.06; 95% CI: 0.84-1.34; P = 0.61). Among CHEK2 carriers, the 15-year survival for women who had an oophorectomy was 86.3% and for women who did not have an oophorectomy was 72.1% (adjusted HR = 0.59; 95% CI: 0.38-0.90; P = 0.02). Among controls, the 15-year survival for patients who had an oophorectomy was 84.5% and for women who did not have an oophorectomy was 77.6% (adjusted HR = 1.03; 95% CI: 0.66-1.61; P = 0.90). CONCLUSION: Among women with breast cancer and a CHEK2 mutation, oophorectomy is associated with a reduced risk of death from breast cancer.

Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study.

BACKGROUND: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest. METHODS: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed. RESULTS: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05). CONCLUSIONS: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor.

BACKGROUND: There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs. METHODS: The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated. RESULTS: The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45-15.43, p=0.01). CONCLUSIONS: Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required.

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.

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.

PALB2 mutations and prostate cancer risk and survival.

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.

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

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.

Genetic predisposition to male breast cancer in 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.

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

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

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

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

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

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

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

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.

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

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.