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.

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.

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

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.

Selected features of breast and peritoneal cancers diagnosed in BRCA1 carriers after risk-reducing salpingo-oophorectomy.

BACKGROUND: Since more than two decades Risk-reducing salpingo-oophorectomy (RRSO) is recommended and widely accepted by BRCA1/2 carriers as a method reducing ovarian cancer risk and improving survival rate. After RRSO, there remains a risk of breast cancer and peritoneal cancer. The characteristics of these neoplasms are not well known. In this study, we determined the selected parameters such as age at cancer diagnosis, time from RRSO to the diagnosis of cancer, and significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up. METHODS: The material comprised of 195 BRCA1 carriers who performed RRSO between years 1999-2012. In this period, 16 patients developed cancer (6-primary breast cancer, 3-contralateral breast cancer, 5-relapse of breast cancer, 2-peritoneal cancer). They were subject of the further analysis. RESULTS: During the follow-up period mean age of patients after RRSO at the time of cancer diagnosis was 53.19. The mean age of patients diagnosed with primary breast cancer was 50, contralateral breast cancer - 58.67, recurrence of breast cancer - 51 and peritoneal cancer 60. The mean time periods from RRSO to the diagnosis of primary, contralateral, recurrence breast cancer were 53, 58.67 and 25,4 months respectively and of peritoneal cancer 46 months. BRCA1 c.5266dupC mutation carriers demonstrated significantly shorter time of cancer development compared to patients carrying c.181T > G and c.4035delA mutations. Peritoneal cancer was only observed in two c.181T > G BRCA1 mutation carriers. CONCLUSIONS: The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.

Clinical efficacy of p16/Ki-67 dual-stained cervical cytology in secondary prevention of cervical cancer.

Cervical cancer is the third most common malignant neoplasm in women worldwide. HPV infection is the necessary factor for the cancer to develop. HPV DNA can be integrated into the genome of squamous epithelium and cause transcription of the viral oncoproteins and development of invasive cancer within 15-20 years. We assessed ICC co-expression of p16/Ki-67 proteins in smears collected from the uterine cervix and the association between p16/Ki-67 co-expression and cytologic and histologic results. Samples were collected from 93 women using liquid based cytology (LBC). Two microscopic slides were prepared: for Papanicolaou staining and ICC staining. Biopsy samples were collected from 43 women. Diagnosis of CIN 2+ was the endpoint of the study. p16/Ki-67 positive cells were found in women with: 1) a cytology result of ASC-US (3.59%), LSIL (2.22%), ASC-H (21.92%), HSIL (33.18%), SCC (72.22%) or NILM (3.44%); 2) a histopathologic result of CIN 1 (2.13%), CIN 2 (19.93%), CIN 3 (23.22%), SCC (69.72%) or normal histology (7.58%). p16/Ki-67 dual staining can increase the efficiency of screening methods and indicate women in whom further diagnostic procedures are required or those with extremely low risk of cancer. Sparing protocols will have a significant role in women of reproductive age.

Implementation of an enhanced recovery after surgery (ERAS) protocol in a gynaecology department - the follow-up at 1 year.

AIM OF THE STUDY: An ERAS protocol provides the latest perioperative care principles, whose primary aim is to reduce complication rates, and therefore mortality. The aim of this study is to establish the progress of the ERAS pathway implementation in our gynaecology department. MATERIAL AND METHODS: This was a retrospective analysis of two sets of 100 consecutive medical records: patients treated before (PRE-ERAS) and after (ERAS) introduction of the ERAS protocol. All patients were comparable and all underwent major gynaecological surgery. Patients as well as medical and nursing staff were informed about the proposed preparation, surgical management and postoperative routine. RESULTS AND CONCLUSIONS: Patients were given supper and drank water during the night. Laparoscopic surgery was used in 44% and spinal anaesthesia was given for open surgery in 43 study patients. Use of drains was reduced only by 23%, bowel preparation by 15%. Intravenous fluid administration was reduced by 22%. Use of postoperative morphine was minimised to 12 patients. Postoperative nausea was managed with the regular use of anti-emetics. Anti-coagulation was given to 80% of the study group. Difficulties in the introduction of the ERAS protocol were due to refusal by some patients to mobilise and eat early postoperatively. Patients in the ERAS programme group were discharged earlier.Further information about the ERAS protocol in the media would facilitate patients' education among conservative society. In order to introduce new and innovative treatment methods, one has to take into account the cultural and ideological factors, especially when patient involvement is essential.

Can ROMA algorithm stratify ovarian tumor patients better when being based on specific age ranges instead of the premenopausal and postmenopausal status?

After several years of research, HE4 was found to be characterized by slightly worse sensitivity but significantly higher specificity as compared with CA125. Further studies led to the diagnostic potential of both markers (CA125 and HE4) being combined in a single risk of malignancy algorithm (ROMA) algorithm. The objective of this study was to assess the diagnostic capabilities of the ROMA algorithm using age ranges instead of dichotomization of patients according to the pre- and postmenopausal status. A total of 413 female patients were included in the study, including 162 premenopausal and 251 postmenopausal women. Calculation of the final ROMA values was achieved by means of stepwise reduction of coefficients in the proposed formula of: %ROMA = exp(PI)/[1-exp(PI)]*100) and PI = A + W(HE4)(*)ln(HE4) + W(CA125)(*)ln (CA125) and the arrangement of values with consideration to the age group, HE4 level, differentiation of modification, and directional coefficients as well as determination of individual deviations affecting the widening of the median. The cutoff value of modified algorithm ROMA P for the entire study population was calculated from receiver operating characteristic (ROC) curve and DeLong method at the levels of 23.5 %. Marked higher sensitivity and negative predictive value (NPV) values are observed for the standard ROMA algorithm while higher specificity and positive predictive value (PPV) values are observed for the modified algorithm ROMA P. The proposed age-related modification of algorithm calculation does not require the patients being dichotomized according to their pre- or postmenopausal status, and satisfactory diagnostic values may be obtained using a single cutoff point for the entire population.

The presence of prostate cancer at biopsy is predicted by a number of genetic variants.

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

Conservative treatment of a young patient with thyroid carcinoma in adult ovarian teratoma - case report.

The cystic mature teratomas, including dermoid cysts, are one of the most frequently occurring benign ovarian tumors diagnosed in female patients. The process of neoplastic transformation in mature dermoid cysts is applicable only to 1-2% of cases. In our article, we present a rare case of thyroid carcinoma development in adult teratoma in 21-year-old patient. The young age, certain pathomorphological features and clinical data (small size of neoplastic lesion, correct values of tumour markers, unilateral character, regular levels of thyreoglobulin and absence of any significant deviations in imaging examinations), were the basis for attempting to apply the conservative treatment both in the scope of gynecological surgery and in the supplemental endocrinological therapy. In the patient, the one-sided adnexectomy was performed, considering pathological lesions on the adnexa, as well as the other ovary dermoid cyst was enucleated, without the hysteroctomy procedure. Considering the lack of any morphological lesions and functional changes relating to thyroid gland, the treatment was not radicalised in this scope, either. At present, one year after the primary operation treatment, the patient does not manifest any disease symptoms, whereas the other ovary, in the follow-up ultrasound examinations, shows normal size and echostructure. The thyroid-stimulating hormone (TSH) suppression keeps being applied.

A rare case of peritoneal disseminated angiosarcoma 20 years after ovarian cancer diagnosis.

Angiosarcoma is a rare form of sarcoma which may be either a primary tumor or it may result from previous irradiation because of another tumor. In this paper, we present a case of a female patient diagnosed as having peritoneal disseminated angiosarcoma 20 years after ovarian cancer treatment (surgery, chemotherapy and radiotherapy). The case was very atypical because of an extremely rare peritoneal location and disseminated nature of the changes. Based on the initial histological picture, poorly differentiated cancer metastasis was diagnosed, suggesting a recurrence of the ovarian cancer that had been diagnosed earlier. The time elapsed from the ovarian cancer diagnosis, history of the previous irradiation and concentration of tumor markers were the only additional clinical data provided to the pathologists, which ultimately contributed to a correct diagnosis. The case we present herein shows and emphasizes the importance of proper communication between a clinician and a pathologist, which is a prerequisite for a correct diagnosis and, consequently, for proper treatment of patients. It also confirms the high specificity of the HE4 (human epididymis protein 4) marker in the monitoring of ovarian cancer, which was within normal limits in spite of peritoneal tumor dissemination.

Association of common WRAP 53 variant with ovarian cancer risk in the Polish population.

Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogenesis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53-TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53-WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.

[Characteristics of selected clinical features in BRCA1 mutation carriers affected with breast cancer undergoing preventive female genital tract surgeries]. / Charakterystyka wybranych aspektów klinicznych u kobiet, nosicielek mutacji genu BRCA1 poddanych operacjom profilaktycznym narzadu plciowego leczonych uprzednio z powodu raka piersi.

AIM: Evaluation of patient age and time of the prophylactic surgery as well as incidence of genital cancers and precancerous states observed in histopathology of the postoperative material from BRCA1 gene mutation carriers previously treated for breast cancer. MATERIAL AND METHODS: 206 carriers of one of the three most common BRCA1 gene mutations (5382insC, C61G and 4153delA) in the Polish population, who were offered the option of prophylactic salpingo-oophorectomy The study group comprised 85 patients with the diagnosis of breast cancer before gynecological preventive surgery The study group was further divided into two subgroups for more detailed assessment of the tested variables. The first subgroup included 67 patients with breast cancer (unilateral or bilateral synchronous). The second subgroup included 18 patients with bilateral metachronous (the second diagnosis of breast cancer was at least 12 months after the first breast cancer diagnosis). The control group consisted of 121 patients with no cancerous lesions before preventive gynecologic surgery The patients undergoing prophylactic treatment had no prior symptoms in female sexual organ and no changes in the diagnostic tests. RESULTS: The patients with a history of breast cancer underwent genetic testing and preventive surgery of the genital tract at a significantly later age than controls (respectively p = 0.0003, p = 0.0006). The patients with bilateral metachronous breast cancer underwent preventive surgery significantly earlier (p = 0.03). There was a trend indicating a 2.5 times higher risk of developing ovarian cancer among BRCA1 mutation carriers who had already been diagnosed and treated for breast cancer when compared to women without breast cancer diagnosis. The incidence of other genital cancers and precancerous states in BRCA1 gene mutation carriers with history of breast cancer was not statistically significant as compared to controls. Data on the clinical stage, morphological grade, histological type, age and type of pathology and the type of BRCA1 gene mutation did not show a statistically significant difference between the groups. CONCLUSIONS: Each patient diagnosed with breast cancer should be strongly recommended a genetic test to reduce adverse consequences resulting from postponing the test and, if applicable, the preventive operation until later in life. Preventive surgery should be considered especially in BRCA1 gene mutation carriers previously treated for breast cancer because of the increased risk of ovarian cancer

The HOXB13 p.Gly84Glu mutation is not associated with the risk of breast cancer.

Recently, the HOXB13 gene has been shown to be a susceptibility gene for prostate cancer. HOXB13 is overexpressed in breast cancer tissues and HOXB13 expression in combination with low expression of IL17BR is predictive for a tamoxifen response in ER-positive breast cancers. Based on observations, we hypothesized that the HOXB13 p.Gly84Glu mutation might be associated with breast cancer risk. We genotyped this mutation in the germline DNA of 4,037 women with breast cancer (including 1,082 familial cases) and in 2,762 controls from Canada and Poland. Seven heterozygous carriers of the HOXB13 p.Gly84Glu mutation were found in the cases (0.17 %) compared to four carriers among the controls (0.14 %; OR = 1.2, 95 % CI = 0.34-4.1, p = 1.0). Only one of the seven carriers had a family history of breast cancer. This study does not support the hypothesis that women who carry the HOXB13 Gly84Glu mutation are at increased risk of breast cancer.

Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: A Reappraisal.

BACKGROUND: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. METHODS: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. RESULTS: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34-0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87-1.70; P = 0.26). CONCLUSIONS: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. IMPACT: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

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.

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.

The role of lipocalin-2 serum levels in the diagnostics of endometrial cancer.

BACKGROUND: Endometrial cancer is one of the most common tumor of the woman genital organs. OBJECTIVE: The goal of this study was to determine the lipocalin-2 levels in patients with endometrial cancer compared to those with normal endometrium or mild endometrial pathologies. METHODS: Study included 123 patients with BMI > 21 kg/m2 who were admitted due to abnormal bleeding, in which 52 patients with endometrial cancer. The NGAL, CA125, HE4 serum levels were determined for all patients. RESULTS: Significantly lower median NGAL serum levels were found in a group of patients with normal endometrium compared to the endometrial cancer group, p= 0.006. NGAL protein area under ROC curves value as a diagnostic test, differentiating between endometrial cancer and other benign changes endometrium is AUC - 0.81 (p< 0.00001). The NGAL protein had a high sensitivity in all patients included in the analysis: 84% vs. 82% in pre-menopausal patients, and 81% in postmenopausal women with a specificity of 78%, 80% and 87%, respectively. The independent variable for FIGO and model logistic regression proves that NGAL is statistically significant (p= 0.000602), the odds ratio is 3.66. The model for grading shows, that NGAL increase by one ng/ml increases risk chances by 2.32 times in diagnosis with less cancer differentiation. CONCLUSIONS: Our preliminary studies demonstrate that lipocalin-2 may be of value in the diagnostics of uterine body cancers.

Ovarian cancer risk in Polish BRCA1 mutation carriers is not associated with the prohibitin 3' untranslated region polymorphism.

BACKGROUND: The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB) gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations. METHODS: To investigate whether the PHB 3'UTR polymorphism also modifies hereditary ovarian cancer risk, we performed a case-control study among Polish women carrying one of the three common founder mutations (5382insC, 300 T > G, 4154delA) including 127 ovarian cases and 127 unaffected controls who had both breasts and ovaries intact. Controls were matched to cases by year of birth and BRCA1 mutation. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using conditional and penalized univariable and multivariable logistic regression. RESULTS: A comparison of the genotype frequencies between cases and controls revealed no association of the PHB 3'UTR _CT+TT genotypes with ovarian cancer risk (ORadj 1.34; 95% CI, 0.59-3.11). CONCLUSION: Our data suggest that the PHB 3'UTR polymorphism does not modify ovarian cancer risk in women carrying one of the three Polish BRCA1 founder mutations.

Integrin beta3 Leu33Pro polymorphism increases BRCA1-associated ovarian cancer risk.

Integrins are heterodimeric transmembrane glycoproteins that function as key adhesion and cell signalling receptors. A functional polymorphism in the integrin beta3 subunit encoded by the ITGB3 gene, Leu33Pro, has been shown to modify a variety of traits of beta3-expressing cells. To analyse the role of this functional polymorphism in modifying BRCA1-associated ovarian and breast cancer risks, a case-control study was performed among Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios were calculated using univariate and multivariate logistic regression, taking into account a series of confounding variables, including the presence of related study subjects, that potentially could have biased any association. The results revealed that the ITGB3_Leu33Pro polymorphism was associated with a 2.5-fold increased risk of ovarian cancer, whereas no association with breast cancer risk was found. Thus, it appears that the ITGB3_Leu33Pro polymorphism may potentially increase the risk of ovarian cancer in Polish women with an inherited BRCA1 mutation.

Could HE4 level measurements during first-line chemotherapy predict response to treatment among ovarian cancer patients?

BACKGROUND: This study assessed the prognostic value of HE4 marker measurements at various stages of first-line chemotherapy for ovarian cancer. METHODS: The study consisted of 90 ovarian cancer patients, including 48 women undergoing primary surgical treatment and 42 patients qualified for neoadjuvant chemotherapy. Each patient underwent HE4 and CA 125 level measurements at the time of diagnosis and subsequently as follows: after surgical treatment, after the third course of adjuvant chemotherapy, before interval cytoreductive surgery and after chemotherapy. The HE4 value was assessed based on the PSF, OS, DFS, surgical outcome, two-year survival and platinum sensitivity. RESULTS: Preoperative HE4 levels were a predictor of platinum sensitivity (AUC- 0.644; p = 0.035) and DFS (AUC = 0.637; p = 0.0492). A univariate logistic regression analysis showed that serum HE4 significantly correlated with PFS (baseline results over median HR = 2.96, p = 0.0009; baseline over 75 percentile HR = 2.44, p = 0.0062; normalization after treatment HR = 0.46, p = 0.0125; 50% reduction before IDS HR = 0.64, p = 0.0017). In the multivariate analysis, normalization after treatment and 50% reduction before IDS significantly influenced the PFS (HR = 0.29, p = 0.00008; HR = 0.23, p = 0.0024). The HE4 levels also correlated with the OS as follows: values below the median (HR = 1.88, p = 0.0087), normalization after chemotherapy (HR = 0.08, p = 0.0003), and 50% reduction before IDS (HR = 0.39, p = 0.0496). CONCLUSIONS: The significant effect of the normalization of the HE4 marker after therapy and 50% reduction of HE4 levels before interval cytoreductive surgery on PFS and OS confirmed that HE4 might be an independent prognostic factor of treatment response. HE4 measurements performed during first-line treatment of ovarian cancer may have prognostic significance.