Molecular genetics of breast cancer

During 1994, 129 specimens of chub (Leuciscus cephalus L.) from two localities, polluted--Bolelouc, 80th river kilometer, near the city of Olomouc, and unpolluted--Brodské, 225th river kilometer, near the Lanzhot on the Morava river, were examined for metazoan parasites. Altogether 38 metazoan parasite species including helminths, leeches and glochidia belonging to 14 genera were found, 34 in the case of unpolluted locality (Brodské) and 28 in the polluted one (Bolelouc). In both localities, 24 parasite species (Dactylogyrus folkmanovae, D. naviculoides, D. prostae, D. vistulae, D. vranoviensis, Gyrodactylus carassii, G. gasterostei, G. gracilihamatus, G. scardiniensis, G. vimbi, Gyrodactylus sp., Paradiplozoon ergensi, P. homoion, P. megan, Paradiplozoon sp., Caryophyllaeus brachycollis, Diplostomum spathaceum--larval stage, Philometra abdominalis, Acanthocephalus anguillae, Pomphorhynchus laevis and Glochidium sp.) were found, 10 (D. crucifer, D. nanoides, G. hemibarbi, G. lamberti, G. leucisci, G. lomi, P. rutili, C. fennica, A. imitans, S. bramae) were identified solely in the unpolluted locality Brodské and 4 (D. fallax, G. laevis, P. ovata, G. kearni) parasite species were found only in the polluted locality Bolelouc. Differences in parasite species richness, the level of dominance, the structure of core and in satellite species were observed. Current methods of statistical evaluation were used.     

Psychological aspects of predictive genetic diagnosis in breast and ovarian carcinoma

Mutations on the genes BRCA1 and BRCA2, that predispose women to breast and ovarian cancer were localised in 1990 (Hall et al. 1990, Narod et al. 1991). With the improvement of the test procedures questions concerning the pros and cons of genetic diagnostic are growing in importance, especially because there are only few scientific studies on the social and psychological consequences of this development. In this article the demands to be made on genetic counselling, the present practice of tests employed in Germany and some "typical" problems of the decision and the consequences of the tests are described.     

Specific worry about breast cancer predicts mammography use in women at risk for breast and ovarian cancer.

This longitudinal study examined predictors of mammography use among women with a family history of breast cancer participating in a risk assessment and surveillance program (N?=?213). Assessed were background variables (age, prior mammography utilization), cognitive variables (perceived vulnerability), and affective variables (cancer worry and general distress). Results of logistic regression analyses predicting adherence 1 year after baseline contact, in which variables of prior utilization, feelings of vulnerability, and general distress were controlled for, indicated that and age were significant predictors of mammography adherence. Results suggest that moderate levels of cancer worry facilitate, rather than undermine, adherence. The results have implications for the construction of educational messages that should be designed to acknowledge feelings of cancer-specific worry and to provide guidance in health protective behaviors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A novel protease homolog differentially expressed in breast and ovarian cancer

BACKGROUND: Using differential display (DD), we discovered a new member of the serine protease family of protein-cleaving enzymes, named protease M. The gene is most closely related by sequence to the kallikreins, to prostate-specific antigen (PSA), and to trypsin. The diagnostic use of PSA in prostate cancer suggested that a related molecule might be a predictor for breast or ovarian cancer. This, in turn, led to studies designed to characterize the protein and to screen for its expression in cancer. MATERIALS AND METHODS: The isolation of protease M by DD, the cloning and sequencing of the cDNA, and the comparison of the predicted protein structure with related proteins are described, as are methods to produce recombinant proteins and polyclonal antibody preparations. Protease M expression was examined in mammary, prostate, and ovarian cancer, as well as normal, cells and tissues. Stable transfectants expressing the protease M gene were produced in mammary carcinoma cells. RESULTS: Protease M was localized by fluorescent in situ hybridization analysis to chromosome 19q13.3, in a region to which other kallikreins and PSA also map. The gene is expressed in the primary mammary carcinoma lines tested but not in the corresponding cell lines of metastatic origin. It is strongly expressed in ovarian cancer tissues and cell lines. The enzyme activity could not be established, because of difficulties in producing sufficient recombinant protein, a common problem with proteases. Transfectants were selected that overexpress the mRNA, but the protein levels remained very low. CONCLUSIONS: Protease M expression (mRNA) may be a useful marker in the detection of primary mammary carcinomas, as well as primary ovarian cancers. Other medical applications are also likely, based on sequence relatedness to trypsin and PSA.     

Molecular pathology of breast cancer and its application to clinical management

Breast cancer is a major cause of morbidity and mortality in women in many parts of the world. Breast carcinomas are heterogenous in their biological and clinical behaviour and a greater understanding of how they develop and progress could lead to more directed forms of screening and therapy. It is important to determine the molecular mechanisms underlying the natural history of breast cancer. Developments in the techniques for molecular analysis have meant that they can now be applied to a large range of clinical material such as cytological preparations and fixed, embedded material, so increasing the potential for relating any molecular alterations to clinical behaviour and response to therapy. In this review we consider recent developments in three areas of importance to breast cancer; genetic analysis-oncogenes, tumour suppressor genes, loss of heterozygosity, microsatellite instability, familial breast cancer; steroid receptors, oestrogen regulated proteins, epidermal growth factor receptor, growth factors particularly transforming growth factor beta; and cell adhesion, invasion and metastasis-E-cadherin, integrins, proteases. These are discussed in relation to potential for screening, prognosis and treatment.     

Molecular genetic events in the development and progression of ovarian cancer in humans

Ovarian tumor development is characterized by specific clinical and pathological features that provide an interesting model of carcinogenesis: first, the pre-invasive and even invasive lesions are difficult to detect; second, a group of cases with a known familial predilection constitute an important heredltary model of carcinogenesis; and third, the category of morphologically borderline ovarian tumors (tumors of low malignant potential) poses several unanswered questions such as: what histologic criteria should be used for their diagnosis; what is their natural history; and what is their molecular relationship to invasive tumors? Recently, molecular studies have contributed to a better understanding of the biology of these tumors, their behavior in vivo, and their response to therapy. This article summarizes the most recent molecular advances.     

Oral contraception and risk of cancer. Epidemiological aspects of breast and gynecological cancers

Oral contraceptives are now widely used by healthy women. Their safety for long-term use is an important issue that has been addressed by numerous epidemiological studies. The single main question about the safety of oral contraceptives use is its potential effect on the development of breast cancer. Several meta-analysis have reviewed all published studies. They provide a reassuring picture: oral contraceptive use does not appear associated with breast cancer. However, increased risks have been identified in specific population for long-term users by young women or before the first full term pregnancy. The use of combined oral contraceptives is associated with lower risks both of endometrial cancer and ovarian cancer. Because of methodologic problems, the results on the risk of cervical cancer and its precursors remain unclear.     

Metastatic gastric cancer arising from breast carcinoma: endoscopic ultrasonographic aspects

Linitis plastica of the stomach was diagnosed in four patients. Endoscopic ultrasonography (EUS) was performed in four cases; they were monitored by EUS and had their treatment adapted accordingly. According to the present study, the typical criteria of gastric linitis at EUS are: (a) rigidity of the gastric wall; (b) a wall thickness exceeding 6 mm; (c) a second enlarged layer marginally more echogenic than the fourth hypoechogenic layer (muscularis propria); (d) a third hyperechogenic enlarged layer; and (e) a poor demarcation between layers. Gastric linitis appears more likely to be specific metastasis from lobular breast carcinoma. In most of the follow-up cases, EUS showed correlation with a subsequent decrease of the CA15.3 level. At present, EUS seems to be the most effective and least invasive examination for clinical diagnosis and treatment surveillance of secondary gastric linitis arising from infiltrating lobular carcinoma (ILC) of the breast.     

Some genetic aspects of ovarian tumors

BACKGROUND: Propranolol and isosorbide-5-mononitrate (ISMN) are increasingly used in the prophylaxis of variceal haemorrhage in cirrhosis. However, recent studies have suggested that these drugs may compromise renal function, possibly by reducing renal blood flow. AIMS: To assess the acute effects of propranolol and ISMN on renal blood flow and other haemodynamic parameters in cirrhosis. PATIENTS AND METHODS: Twenty six cirrhotic patients were given either 80 mg propranolol, 20 mg ISMN, or a combination of the two drugs. Unilateral renal blood flow (RBF), azygos blood flow (AZBF), hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and heart rate (HR) were recorded prior to and one hour after drug administration. RESULTS: Propranolol caused a reduction in HR (p < 0.005), AZBF (p < 0.01), and HVPG (p = 0.05), but no change in MAP or RBF (454.1 (77.3) versus 413.9 (60.3) ml/min). ISMN reduced MAP (p < 0.005) and HVPG (p < 0.01), but had no effect on HR, AZBF, or RBF (302.5 (49.4) versus 301.7 (58.8) ml/min). Combined treatment reduced MAP (p < 0.005), AZBF (p < 0.05), and HVPG (p = 0.002), but HR and RBF (419.2 (62.6) versus 415.1 (61.1) ml/min) remained unchanged. CONCLUSIONS: Despite the anticipated changes in other haemodynamic parameters, acute propranolol and/or ISMN administration did not reduce RBF. These drugs do not seem to compromise RBF in cirrhosis.     

Low incidence of BRCA1 mutations among Italian families with breast and ovarian cancer

Most familial breast or ovarian cancers are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. The cloning of these genes has opened a new era for the genetic counseling of women with a family history of breast or ovarian cancer. To estimate the incidence of detectable BRCA1 mutations and to define the eligibility criteria for genetic testing in the Italian population, a total of 53 patients belonging to 46 families clustering multiple cases of breast and/or ovarian cancer were investigated. Seven families presented with ovarian cancer only, 16 had both ovarian and breast cancers, and 23 were characterized by breast cancer only. Using a combination of protein truncation test (PTT) and single strand conformational polymorphism (SSCP) analysis followed, when necessary, by direct sequencing, we found 8 distinct mutations, 2 of these not reported before. Five frameshift and 2 nonsense mutations led to a truncated protein. One mutation was a missense substitution involving a cysteine in the zinc finger domain. One variant creating an ETS binding site in intron I was found but its role was not defined. The percentage of families carrying mutations was 17%. Among the families characterized by ovarian cancer only and by breast and ovarian cancer, the percentage of BRCA1 mutations was 57% and 12.5%, respectively. In contrast, the percentage of altered BRCA1 in families with only breast cancers was 9%. In the 46 Italian families studied, BRCA1 mutations were detected in fewer kindreds than those previously hypothesized based on linkage analysis, especially when these were characterized by breast cancers only. Our results indicate that families with a low number of cancer patients should be referred for BRCA1 genetic testing mainly when ovarian cancer is present.     

Developmental and endocrine aspects of normal ovarian aging

The fluorescence plus Giemsa (FPG) and fluorescence in situ hybridization (FISH) techniques have been used to determine, respectively, the frequencies of sister chromatid exchanges (SCEs) and stable chromosome aberrations (translocations) induced by different concentrations of BrdU in the Chinese hamster ovary cell mutant EM9 and its parental line AA8. The results indicate that BrdU induced a high frequency of SCEs and translocations in EM9 as compared with AA8, and that the translocation/dicentric ratio was also higher in the mutant cell line than in the parental cell line in both untreated and BrdU-treated cultures. These observations may indicate a possible relationship between the molecular mechanisms involved in the formation of SCEs and translocations.     

Distress and psychiatric morbidity among women from high-risk breast and ovarian cancer families.

This study assessed psychological distress and psychiatric disorder in high-risk women enrolled in a hereditary breast and ovarian cancer registry, and it evaluated the concordance between self-report data and interview-based psychiatric diagnosis. A sample of 464 women completed the Hopkins Symptom Checklist-25 and were interviewed using modules of the Structured Clinical Interview for DSM-IV. Level of psychological distress and the prevalence of psychiatric disorder were low and in the range that would be expected for a sample of community-residing women. Screening proved inefficient: Less than 10% of distressed women met criteria for a clinical disorder. High-risk women seeking genetic testing in research settings may not require extensive psychological screening and diagnostic assessment. Caution is expressed about possible self-selection biases in women enrolled in hereditary cancer registries. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Molecular pathology of ovarian carcinomas

Two patients with lysinuric protein intolerance (LPI) had near-fatal generalized varicella infection with severe interstitial pneumonitis, hepatitis, decreased platelet count, bleeding and hypoalbuminaemia. Active haemolysis resulted in anaemia and massive haemoglobinuria. Serum lactate dehydrogenase activity and ferritin concentration, which in patients with LPI in normal circumstances exceed the upper reference values 3-folds to 10-fold, increased to > 10,000 U/L and > 10,000 micrograms/L, respectively. The patients were treated with fresh frozen plasma, red-cell transfusions and intravenous acyclovir for 14 days, and recovered clinically in a month. Retrospectively, 3 of the 32 other known Finnish patients with LPI had had varicella infection that had been more severe than that in the other children in the family or in subjects in the neighbourhood and had led to hospital admission. Varicella antibodies were measured in 24 patients; 5 had no antibodies and 5 had very low antibody titres. Primary vaccination of three patients with living varicella vaccine increased antibody titres measurably in one patient. We suggest that patients with LPI who have no varicella zoster antibodies should be treated with acyclovir if exposed to varicella and should be (re)vaccinated against chickenpox.     

Molecular aspects of preterm labor

Preterm birth is a major problem in clinical obstetrics, occurring in approximately 10% of all pregnancies, and leading to 75% of early neonatal mortality and morbidity. Studies in our laboratory have examined the neuroendocrine mechanisms by which the fetus, through activation of the hypothalamic-pituitary adrenal axis, provides the stimulus to the onset of parturition. Maturation of this axis occurs prematurely in response to stimuli such as stress. Stress induced activation of HPA function in human pregnancy, may lead to increased output of corticotropin-releasing hormone (CRH) from placenta and fetal membranes. CRH is one of the agonists that acts in concert with increased prostaglandin biosynthesis to provide the stimulus to myometrial contractility in late gestation. Recent studies have also recognized that approximately 15% of patients in idiopathic preterm labor present, with deficiency of the major prostaglandin metabolizing enzyme in the fetal membranes, particularly chorionic trophoblast. Understanding these processes may lead to new methods of managing the patient presenting in preterm labor.     

A lump in the breast. A rare first symptom of ovarian cancer

The breast is an uncommon site for metastasis from extramammary primaries. A 43-year-old woman presented with a lump in the left breast. A tumour with atypical microcalcifications was seen on the mammogram. Needle aspiration cytology revealed adenocarcinoma cells. The final histological diagnosis was papillary adenocarcinoma with psammoma bodies, probably secondary to an ovarian carcinoma. A bilateral carcinoma of the ovaries was subsequently diagnosed and treated. A mammary tumour with an atypical growth pattern and the absence of in situ carcinoma should always prompt the pathologist to considering the possibility of a metastatic tumour even though this is a rare occurrence. Earlier recognition of metastatic tumours to the breast may result in initiation of appropriate therapy and will preclude unnecessary surgical procedures.     

Genetic epidemiology of breast and ovarian cancers

Most civilian and military air traffic control facilities in the United States use rapid rotation shift schedules. These schedules have generally been chosen for social reasons. Safety concerns have been raised because the air traffic controllers (ATCs) often carry an acute sleep debt onto the night-shift where they have little active work to do as they sit in the dark at the nadir of their circadian rhythms. This paper reviews advancing and delaying rapid shiftwork schedules, ATC workload factors as they relate to error rates and safety, and potential countermeasures. Recent studies indicate that ATC performance declines on the night-shift and that ATCs may be falling asleep while on-duty. There is indirect evidence that ATC error rates are highest on the night-shift. There are only limited studies which have evaluated potential countermeasures. The operational significance of the problems associated with ATC shiftwork is not yet clear. Further study is needed.