Preoperative Serum Levels of PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 in the Diagnosis of Endometrial Cancer.

(1) Background: It is relevant to find new diagnostic biomarkers for endometrial cancer. This study aimed to investigate whether PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 could be considered new useful markers for diagnosis and survival of endometrial cancer. (2) Methods: A total of 93 women diagnosed with endometrial cancer (EC) and 66 patients with non-cancerous endometrial lesions (NCEL) were included in this study. (3) Results: Median serum levels of PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 were significantly higher in the EC group compared to the NCEL group (for PDGF-AB, PDGF-BB, TGF-α and ANG-2, p = 0.0000; for EGF, p = 0.0186). The cut-off level of PDGF-AB was set at 127.69 pg/mL with a sensitivity of 87.1% and a specificity of 66.67% (AUC = 0.78, p < 0.000001). The cut-off level of PDGF-BB was set at 207.86 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.85, p < 0.000001). The cut-off level of TGF-α was set at 33.85 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.82, p < 0.000001). The cut-off level of EGF was set at 934.76 pg/mL with a sensitivity of 83.87% and a specificity of 28.79% (AUC = 0.61, p = 0.018472). The cut-off level of ANG-2 was set at 3120.68 pg/mL with a sensitivity of 72.04% and a specificity of 93.94% (AUC = 0.87, p < 0.000001). (4) Conlusion: It was concluded that all the proteins studied could be potential diagnostic markers in endometrial cancer.

Pilot Study: FSHR Expression in Neuroendocrine Tumors of the Appendix.

Appendix neuroendocrine neoplasm (ANEN) treatment is based on tumor size and proliferation markers. Recently, the role of the follicle-stimulating hormone receptor (FSHR) from the clinical perspective has also been increasingly discussed. The FSHR is expressed in the endothelial cells of both intratumoral and peritumoral blood vessels, where it contributes to neoangiogenesis and blood vessel remodeling. FSHR expression is associated with a range of tumor types, such as gastrointestinal tumors, and it is not detected in healthy tissues located more than 10 mm from the tumor site or in tumor lymphatics. In this study, we evaluated the expression of FSHR and CD31 in the blood vessels of ANENs in females and males with confirmed histopathology. We conducted a quantitative analysis of the immunohistochemical reactions and found a higher number of microvessels in the mucosa and submucosa of neuroendocrine tumors in the appendix. A higher level of FSHR expression was observed in women. Future research should consider whether an elevated number of blood vessels along with a strong pattern of FSHR expression may influence future treatment strategies.

Bladder cancer survival in patients with NOD2 or CDKN2A variants.

PURPOSE: The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains controversial. MATERIALS AND METHODS: We compared the allele frequencies of NOD2 c.3020insC and CDKN2A p.A148T allele in 706 patients with bladder cancer, 410 cases with kidney cancer against two control groups. The Cox proportional hazards model was used to determine whether there were any survival differences between carriers of the NOD2 c.3020insC or the CDKN2A p.A148T variant. RESULTS: Among the three patient subgroups: patients under 60 years of age, non-smokers and a third with histological features of low grade noninvasive papillary bladder cancer, we observed that the c.3020insC allele had a nominal statistically significant effect on survival. We also observed that the NOD2 c.3020insC variant was more frequent in patients with bladder cancer aged between 51 and 60 years. There was some nominal evidence that the CDKN2A p.A148T polymorphism reduced survival in the subgroup of bladder cancer patients under 60 years of age. We observed that in kidney cancer patients, the incidence of the NOD2 variant appeared to be lower in the group aged between 60 and 70 years, however, this was not statistically significant. In addition, in patients with histological features of grade III chromophobic kidney cancer, the c.3020insC allele also appeared to be over-represented but this too was not statistically significant. CONCLUSION: We have shown that the NOD2 c.3020insC allele and the CDKN2A p.A148T polymorphism does not play a role in the survival of patients with bladder cancer.

Germline BRCA1 and BRCA2 mutations and the risk of bladder or kidney cancer in Poland.

INTRODUCTION: The role of the BRCA1 and BRCA2 genes in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of specific founder mutations genes BRCA1 (5328 insC, C61G and 4153 delA) and BRCA2 (C5972T) mutations in bladder and kidney cancer patients from Poland. MATERIALS AND METHODS: We genotyped 1028 patients with bladder cancer and 688 cases with kidney cancer and two control groups. RESULTS: A BRCA1 mutation (all variants combined) was detected in peripheral blood leukocytes in 5 out of 1028 (0.5%) bladder cases and in 17 of 4000 controls (0.4%) (odds ratio [OR], (OR = 1.1; 95% CI 0.42-3.11; p = 1.0). Among 688 unselected kidney cancer cases a BRCA1 mutations was reported in three patients (0.4%) (OR = 1.0; 95% CI 0.29-3.51; p = 1.0). The mutation C5972T in BRCA2 was observed in 54 bladder cancer patients (5.2%) and in 159 of 2791 healthy controls (5.7%) (OR = 0.9; 95% CI 0.66-1.26; p = 0.6). Fifty kidney cancer cases carried a BRCA2 mutation (7.3%) (OR = 1.3; 95% CI 0.93-1.80; p = 0.1). CONCLUSION: In conclusion, we found no difference in the prevalence of BRCA1 and BRCA2 founder mutations between cases and healthy controls. The mutations BRCA1 and BRCA2 seem not to play a role in bladder and kidney cancer development in Polish patients.

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.

Germline HOXB13 mutation p.G84E do not confer an increased bladder or kidney cancer risk in polish population.

INTRODUCTION: The role of HOXB13 in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of HOXB13 p.G84E mutation in bladder and kidney cancer patients from Poland. MATERIALS AND METHODS: 1418 patients with bladder cancer and 813 cases with kidney cancer and 4497 controls were genotyped for HOXB13 p.G84E. RESULTS: p.G84E mutation of HOXB13 gene was detected in three of 1418 (0.2%) bladder cancer cases and in six of 4497 controls (odds ratio [OR], 1.6; 95% CI 0.39-6.36; p = 0.8). Among 813 kidney cancer cases HOXB13 mutations was reported in three patients (0,4%) (odds ratio [OR], (OR = 2,8; 95% CI 0.69-11.11; p = 0.3). In cases with mutations in the HOXB13 gene, the family history of cancer was negative. CONCLUSION: HOXB13 mutation was not associated with bladder or kidney cancer. Mutation p.G84E in HOXB13 seem not to play a role in bladder and kidney cancer development in Polish patients.

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

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

PURPOSE: The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer. MATERIALS AND METHODS: 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (≤60; >61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive). RESULTS: We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02-1.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50-42.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30-4.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02-0.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07-0.76; p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19-3.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12-0.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95-67.7; p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% (p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% (p = 0.5). CONCLUSION: CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma.

Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer.

The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 genes with ovarian cancer risk among unselected patients in Poland. We genotyped 21 recurrent germline mutations in BRCA1 (9 mutations), BRCA2 (4 mutations), RAD51C (3 mutations), PALB2 (2 mutations), and CHEK2 (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 BRCA1 (OR = 40.79, 95% CI: 18.67-114.78; p = 0.29 × 10-15), in BRCA2 (OR = 25.98; 95% CI: 1.55-434.8; p = 0.001), in RAD51C (OR = 6.28; 95% CI 1.77-39.9; p = 0.02), and in PALB2 (OR 3.34; 95% CI: 1.06-14.68; p = 0.06). There was no association found for CHEK2. We found that pathogenic mutations in BRCA1, BRCA2, RAD51C or PALB2 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.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

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

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

Serum HE4, CA125, YKL-40, bcl-2, cathepsin-L and prediction optimal debulking surgery, response to chemotherapy in ovarian cancer.

BACKGROUND: The most important prognostic factor in the ovarian cancer is optimal cytoreduction. The neoadjuvant chemotherapy, an only optional method of treatment in this case and is still the subject of debate. The object of this study was to evaluate the usefulness of markers: CA 125, HE4, YKL-40 and bcl-2 as well as cathepsin L in predicting optimal cytoreduction and response to chemotherapy. METHODS: Sera were secured preoperatively. The division into groups was performed retrospectively depending on the method of treatment (surgery vs neoadjuvant chemotherapy) as well as on response to chemotherapy (sensitive vs resistant vs refractory). Comparisons were made between groups, and the diagnostic usefulness of tested proteins was examined. RESULTS: We found that statistically significant differences between primary operated patients and patients undergoing neoadjuvant chemotherapy were applicable only to the tumour markers (CA125 1206.79 vs 2432.38, p=0.000191; HE4 78.87 vs 602.45, p=0.000004; YKL-40 108.13 vs 203.96, p=0.003991). Cathepsin-L and Bcl-2 were statistically insignificant. The cut-off point values were determined for the CA 125 (345 mIU/ml), HE4 (218.43 pmol/L) and YKL-40 (140.9 ng/ml). The sensitivity, specificity, PPV and NPV were as follows: CA125 (83.3%; 75%; 80.6%; 78.3%), HE4 (86.6%; 91.3%; 92.9%; 84%) and YKL-40 (75%; 83.3%; 84%; 74.1%). CONCLUSION: Among the tested proteins the HE4 marker appears to be helpful in forecasting of optimal cytoreduction and possibly also of the prediction of response to platinum analogues used in first-line treatment of ovarian cancer.

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

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

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

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

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

The CYP17A1 -34T > C polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (-34 T > C; rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n = 1693) or BRCA2 (n = 528) germline mutations from seven centers were genotyped for the -34 T > C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89-1.17, p = 0.74) and 1.10 (95% CI 0.72-1.67, p = 0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94-1.46, p = 0.17) and 0.91 (0.31-2.67, p = 0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the -34 T > C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland.

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome characterized by a high risk of diffuse stomach cancer and lobular breast cancer. HDGC is caused by germline mutations in the CDH1 gene encoding the E-cadherin which is a member of the transmembrane glycoprotein family responsible for calcium-dependent, cell-to-cell adhesion and plays a fundamental role in the maintenance of cell differentiation and the normal architecture of epithelial tissues. Mutations in the CDH1 gene are detected in 30-46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria. In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC. The entire coding sequence of CDH1 gene was analyzed by sequencing in 86 Polish cancer patients from families fulfilling the modified criteria of HDGC. We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients. In addition, we found four rare sequence variants of unknown significance localized in introns. We did not detect any deleterious mutations of the CDH1 gene. CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria. Further studies of families with HDGC matching the restrictive criteria for HDGC are needed.

BRCA1-associated breast and ovarian cancer risks in Poland: no association with commonly studied polymorphisms.

Polymorphisms in genes involved in DNA repair, steroid hormone biosynthesis/metabolism/signaling, folate metabolism as well as cell growth are prime candidates for possible associations with breast and ovarian cancer risk in women with an inherited predisposition. We investigated 29 polymorphisms in 20 genes encoding key proteins of the above four biological pathways for their breast and ovarian cancer risk modifying effect in Polish women harboring BRCA1 founder mutations. Of the analyzed genes, ERCC2, XRCC1, XRCC2, XRCC3 and Lig4 participate in DNA repair, TP53 in cell cycle check point control, AIB1, AR, COMT, CYP11A1, CYP17A1, CYP19A1, HSD17 and PGR in steroid hormone biosynthesis/metabolism/signaling, TYMS in folate metabolism and HER2, IL6, LRP1, TGFB and TGFBR1 affect cell growth. Using validated methods, we genotyped 319 breast cancer cases, 146 ovarian cancer cases and 290 unaffected controls, all of whom harbored one of three causative mutations in BRCA1. Our results revealed no association of any of the investigated polymorphisms with BRCA1-associated breast or ovarian cancer risk. Thus, it appears that these polymorphisms do not influence disease risk in Polish women carrying one of the three common BRCA1 founder mutations.

Premature menopause in patients with BRCA1 gene mutation.

This study was undertaken with regard to the gonadotropin theory of ovarian cancer advocated in the literature and was designed to disclose specific features of ovarian morphology in carriers of the BRCA1 gene mutation. We enrolled 171 patients and divided them into two groups: A (n=90)--operated for breast cancer (30 patients with and 60 without the BRCA1 mutation); B (n=81)--with the BRCA1 mutation qualified for preventive adnexectomy. According to the authors' classification described herein, some patients without the BRCA1 mutation retained "signs of estrogenization" in menopausal ovaries, revealing the role of estrogens as a factor promoting mammary carcinogenesis in these patients. A tendency to premature menopause was observed in BRCA1 mutation carriers of groups A and B as evidenced by the final menorrhea appearing at a younger age and almost total absence of "signs of estrogenization" in menopausal ovaries. It is concluded from these findings that earlier menopause in carriers of the BRCA1 mutation is associated with hypergonadotropic activity and may predispose to ovarian cancer at younger age.