The impact of an expanded genetic testing program and selective oophorectomy on the incidence of ovarian cancer in West Pomerania.

The aim of the study was to evaluate the impact of a regional population-based genetic testing program on the incidence of ovarian cancer in West Pomerania. Between 1999 and 2010, a total of 37,552 women ages 35 to 70 were tested for three BRCA1 founder mutations at the outpatient genetics clinic of the Pomeranian Medical University in Szczecin, Poland. A total of 641 women were found to carry a mutation (1.7%) and of these, 220 had a prophylactic oophorectomy (34.3%). A total of 12 women had an occult cancer diagnosed at the time of prophylactic oophorectomy (5.5%). We estimate that 26 more ovarian cancers would have been diagnosed by January 2015 in the absence of these oophorectomies and that an additional 25 cancers will be prevented in the future (total 51). During this period, 1611 ovarian cancers were diagnosed in the region; therefore we estimate that approximately 1.6% of ovarian cancers were prevented between 1999 and 2015 by our genetic testing program. We conclude that the prophylactic oophorectomies performed between 1999 and 2010 as a result of widespread BRCA1 mutation testing have reduced the incidence of ovarian cancer in Pomerania by a small amount (about 1.6%), and that the impact of genetic testing will increase in the coming years.

A personalised approach to prostate cancer screening based on genotyping of risk founder alleles.

BACKGROUND: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. METHODS: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs). RESULTS: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). CONCLUSION: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status.

BACKGROUND: Mutations in the BRCA1 (MIM 113705) gene are found in many families with multiple cases of breast and ovarian cancer, and women with a BRCA1 mutation are at significantly higher risk of developing breast and ovarian cancer than are the general public. METHODS: We obtained blood samples and pedigree information from 3568 unselected cases of early-onset breast cancer and 609 unselected patients with ovarian cancer from hospitals throughout Poland. Genetic testing was performed for three founder BRCA1 mutations. We also calculated the risk of breast and ovarian cancer to age 75 in the first degree relatives of carriers using Kaplan-Meier methods. RESULTS: The three founder BRCA1 mutations were identified in 273 samples (187 with 5382insC, 22 with 4153delA, and 64 with C61G). A mutation was present in 4.3% of patients with breast cancer and 12.3% of patients with ovarian cancer. The overall risk of breast cancer to age 75 in relatives was 33% and the risk of ovarian cancer was 15%. The risk for breast cancer was 42% higher among first degree relatives of carriers of the C61G missense mutation compared to other mutations (HR = 1.42; p = 0.10) and the risk for ovarian cancer was lower than average (OR = 0.26; p = 0.03). Relatives of women diagnosed with breast cancer had a higher risk of breast cancer than relatives of women diagnosed with ovarian cancer (OR = 1.7; p = 0.03). CONCLUSIONS: The risk of breast cancer in female relatives of women with a BRCA1 mutation depends on whether the proband was diagnosed with breast or ovarian cancer.

Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland.

Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics.

Clinical features of familial ovarian cancer lacking mutations in BRCA1 or BRCA2.

PURPOSE OF INVESTIGATION: The purpose of the present study was to identify the clinical and pathologic features of ovarian cancers in patients who have a family history of breast or ovarian cancer but who do not have a mutation in the BRCA1 or BRCA2 gene. METHODS: 303 patients with ovarian cancer were reviewed for clinical features and for cancer family histories. After the exclusion of 51 patients known to carry BRCA1 or BRCA2 mutations, 24 patients with familial cancer were compared with 228 patients with non-familial cancer. RESULTS: Patients with familial cancer were more likely to have grade 2 tumors, Stage II disease and to present between ages 51 and 60 than were non-familial controls. Ten of 24 patients in the familial group presented between ages 51 and 60 with a grade 2 tumor compared to 3.0 expected (p = 0.001). CONCLUSIONS: Families of women who present with grade 2 ovarian cancer between the ages of 51 and 60 may have an unidentified ovarian cancer susceptibility gene.

Detection of germline mutations in the BRCA1 gene by RNA-based sequencing.

BRCA1 mutation detection is expensive and has sensitivity limitations, which might at least partially be overcome by RNA-based sequencing. There are claims that RNA tests are unreliable due to differential splicing, exon skipping, or nonsense-mediated mRNA decay that results in either the absence or low expression of mRNA harboring mutations. The major aim of this study was to determine if the application of specific high temperature annealing primers can assure high sensitivity of detection of BRCA1 sequence alterations by cDNA sequencing. The study group comprised 21 Polish cancer families with aggregations of breast and/or ovarian cancer. We detected mutations in 10 out of 21 unrelated patients. These were: nucleotide substitutions (c.309T>C; c.300T>G); nucleotide insertions (c.5382insC) three cases; nucleotide deletions (c.4154delA) one case, (c. 185delAG) one case, (c.3819delGTAAA) two cases; and the deletion of the entire sequence of exon 22, one case. In addition, we identified three transcript variants resulting from alternative splice sites affecting the last six nucleotides of exon 1a (GTAAAG), and the first three nucleotides (CAG) of exon 8 and exon 14. In all cases these were cDNA heterozygous changes. Two of these splice site changes have not been previously described. Sequencing of genomic DNA "exon by exon" did not result in the detection of any additional abnormalities. The sensitivity of our analyses was sufficient to reliably detect mutations without the necessity of tissue culturing to obtain enough template cDNA for analysis.

Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.

We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age <50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively.

[Hereditary ovarian cancer: summary of 5 years of experience]. / Dziedziczny rak jajnika--podsumowanie piecioletnich badan.

UNLABELLED: In 1992 the first Hereditary Cancer Center in Poland has been organized in Szczecin. DESIGN: One of its goals is application of appropriate management in families with hereditary ovarian cancer. The aims of our program include studies of: incidence, clinical characterization, DNA diagnostic tests and efficiency of screening for early detection of hereditary ovarian tumors in North-West Poland. MATERIAL: Our program includes 234 families with 258 cases of ovarian cancers. RESULTS: Site-specific familial aggregation of ovarian cancer was diagnosed in 16 (6.84%) families, breast-ovarian cancer syndrome in 27 (11.54%), Lynch II syndrome in 5 (2.14%) families, undefined cancer family aggregation in 12 (5.13%) families, sporadic ovarian cancers diagnosed age of 44 in 56 (23.93%) families and other sporadic ovarian cancers in 118 (50.4%). In 17 patients with ovarian cancer from families with breast-ovarian cancer syndrome constitutional BRCA-1 gene mutations were studied by sequencing DNA on automated sequencer of PCR products for all 24 exons. In 1 patient constitutional mutation in exone 11 was detected. We found also multiply polymorphic changes. 124 women-members of 116 families with diagnosed hereditary predisposition for ovarian cancer have been studied for asymptomatic tumors by intravaginal USG and evaluation of CA 125 marker every 6 month beginning from 20-25 years of age. Up to now we found 5 cases of benign serous cystadenomas, 3 cases of cystadenomas of borderline malignancy and 1 cases of serous cystadenocarcinoma. CONCLUSIONS: It seems, that particular surveillance program in women from families with hereditary cancers can be the effective way of detection of early ovarian tumors. Clinical characterization of hereditary ovarian cancers in North-West Poland and other countries is similar.

[Major risk factors for endometrial carcinoma]. / Glówne czynniki ryzyka w raku trzonu macicy.

Our results were compared with the results from numerous recent studies concerning important risk factors for the endometrial carcinoma. We revealed that only age more then 50 with conjunction with obesity is the important risk factor. We didn't proved the protection role of the pregnancy emphasized in the literature. The role of others epidemiologic risk factors for the endometrial carcinoma remains still unequivocally explained.

[Ultrasonography, laparoscopy, neoplastic markers--new possibilities of conservative operative treatment for ovarian neoplasms in girls and young women]. / Ultrasonografia, laparoskopia, markery nowotworowe--nowe mozliwosci oszczedzajacego leczenia operacyjnego nowotworów jajnika u dziewczat i mlodych kobiet.

The knowledge of ovarian physiopathology and the employing of modern diagnostic methods (ultrasonography, laparoscopy) allow to avoid to operate patients with functional cysts. Girls and young women should be evaluated individually for ovarian surgical procedures. The operative treatment should be so conservative as possible employing all diagnostic and monitoring methods including specific markers assays.

[Lichen sclerosus in girls--risk group for development of vulvar neoplasms in women]. / Lichen sclerosus u dziewczat--grupa ryzyka rozwoju raka sromu u kobiet?

Lichen sclerosus is one of the vulvar dystrophy, which is rare at children and young women. 20 girls, aged 3 to 14 years, with clinical and histopathological diagnosis--lichen sclerosus without dysplastic lesions--were under the control of The Gynecological Outpatient Clinic of Children and Girls in Szczecin. They were treated with estrogens (estriol with vitamin A--ointment) and vitamin A rich diet. Anti-inflammatory treatment was employed if necessary. After long-term treatment at 8 girls the total recovery was obtained, at 2, clinical symptoms decreased. Other girls are under clinical observation as before. The girls with lichen sclerosus are a risk group of vulvar carcinoma development in mature age.

[Pain in the lumbosacral region in pelvic congestion syndrome in women working under conditions of limited motor activity]. / Bóle odcinka ledzwiowo-krzyzowego kregoslupa w zespole miednicy przekrwionej u kobiet pracujacych w warunkach ograniczonej aktywnosci ruchowej.

The paper deals with the problem of pain in L-S segment of the vertebral column in Pelvic Congestion Syndrome-Pcs. The study covers two groups of women. The studied group comprised 63 seamstresses being employed in piece-work system, requiring great concentration of their attention and precision in producing the elements. That was accompanied by monotony and hypokinesis. The control group was made up of 22 women working in the same material-labour conditions, but in non-compulsory position. The analysis was performed by resorting to specially elaborated method of gynaecological examination elements of ergonomic studies and those of biomechanics. It has been shown that hypokinesis and piece-work claiming far advanced precision, as well as monotomy of the performed activity lead, in consequence, to congestion of organs in the small pelvis. In the investigated material, sacrodynia and hypogastric pain have been found to appear as the main symptoms involving women with Pcs. The material in both groups was selected by eliminating other causes likely to give rise to pain in lumbosacral segment of the vertebral column.

[Introduction of the results of ergonomic studies in clothing factories]. / Wdrozenie wyników badan ergonomicznych w zakladach odziezowych.

Hypokinesis is known to exert a negative effect on human systems, the circulatory, osseo-articular, muscular and many other systems. Ergonomic investigations, performed during five years and covering 1350 women employed at clothing and knitting plants as seamstresses carrying out their work at piece-rate, direct line as well as beltsystem, under the conditions of restricted motorial activity, i.e. under hypokinetic conditions, revealed the occurrence of pelviccongestion syndrome (pcs). Relying on the obtained results of the investigations, the evaluation involved the condition of women's reproductive organ in the context of the integrated state of health of female workers employed as seamstresses at clothing and knitting plants, viewed against the background of professional and sociological problems. Moreover, recommendations were issued as to the treatment of genital organ disorders in women employed under the conditions of restricted motorial activity, and also prophylaxis concerning these disturbances, particularly with regard, to the pelvic congestion syndrome. Elements of reorganization of the health service at the clothing and knitting industry plants have been worked out and described.