Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations

RATIONALE AND OBJECTIVES: The authors have investigated dysprosium [Dy]-DOTA-PAMAM, generation 5 (G = 5) dendrimers as a possible new class of macromolecular T2 contrast agents. The use of DOTA provides a metal complex with greater stability than can be achieved using DTPA as ligand, an important factor in the design of blood pool agents with long half-lives. METHODS: Generation 5 ammonia-core PAMAM dendrimers were linked to the bifunctional ligand p-SCN-Bz-DOTA. After determination of the number of conjugated DOTA molecules by 1H nuclear magnetic resonance, Dy3+ was titrated at a 90% molar ratio. For comparison, single ionic chelates of Dy-DTPA and Dy-DOTA also were prepared. Using a variable field relaxometer, T1 and T2 relaxation times were measured at 13 different field strengths from 0.05 to 1.5 T and temperatures of 3, 10, 20 and 37 degrees C. RESULTS: The synthesis resulted in a preparation with 76 DOTA and 68 Dy3+ ions per dendrimer molecule. The T1 relaxivity values for Dy-DTPA, Dy-DOTA, and the Dy-DOTA-based dendrimer all were independent of field strength, with values between 0.12 and 0.20 mM-1 sec-1. At lower fields (0.05-0.1 T), 1/T2 was identical to 1/T1. At higher fields, however, 1/T2 increased quadratically with field strength, with a strong dependence on temperature. The field-dependent component of 1/T2 was up to three times higher for the Dy-DOTA-based dendrimer compared with the single chelate molecules, with coefficients of 0.37 to 0.03 sec-1/Tesla2 for T = 3 to 37 degrees C. CONCLUSIONS: The results are interpreted with the "inner sphere" theory of susceptibility effects (Curie spin relaxation). The large temperature dependence suggests that the dominant mechanism of relaxation is the contact interaction effect, with the proton residence time as the primary time constant. This largely unexplored relaxation mechanism has the potential to create a new class of T2-selective contrast agents.     

Double heterozygosity for mutations in the BRCA1 and BRCA2 genes in a breast cancer patient

BACKGROUND: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 confer substantial increased lifetime risk for breast cancer, and in the case of BRCA1, for ovarian carcinoma as well. These two genes alone account for the vast majority of hereditary breast cancer families. Numerous mutations have been described in each gene, the majority of which are small insertions or deletions resulting in expression of a truncated protein. MATERIALS AND METHODS: Several common mutations can be detected using a polymerase chain reaction-mediated, site-directed mutagenesis assay, which transforms the amplicon derived from either the wild-type or mutant allele by adding or removing a restriction endonuclease site. We screened 49 putative sporadic breast tumors using this methodology, targeting four BRCA1 mutations (185delAG, 5382insC, R1443X, and E1250X) and a single BRCA2 mutation (6174delT). RESULTS: Using the polymerase chain reaction-mediated, site-directed mutagenesis assay, we identified two mutations, namely, a 185delAG mutation (BRCA1) and a 6174delT mutation (BRCA2). Interestingly, these two mutations were found in the same sample. None of the remaining 48 breast tumors showed evidence of these mutations. Allele-specific oligonucleotide probes were then employed in conjunction with the Universal GeneComb Test Kit, which confirmed the presence of mutations. CONCLUSIONS: Our data suggest that the common germline BRCA1 and BRCA2 mutations are infrequently encountered in sporadic breast cancers. The one case with dual BRCA1 and BRCA2 mutations suggests that this tumor may be hereditary in origin, despite the lack of a positive family history. Double heterozygosity for mutations in BRCA1 and BRCA2 may have increasingly significant implications with regard to predisposition to breast cancer.     

Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient

Nitric oxide (NO) has been implicated as a modulator of the vascular effects of angiotensin II (ANG II) in the kidney. We used a NO-sensitive microelectrode to study the effect of ANG II on NO release, and to determine the effect of selective inhibition of the ANG II subtype I receptor (AT1) with losartan (LOS) and candesartan (CAN). NO release from isolated and perfused renal resistance arteries was measured with a porphyrin-electroplated, carbon fiber. The vessels were microdissected from isolated perfused rat kidneys and perfused at constant flow and pressure in vitro. The NO-electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. ANG II stimulated NO release in a dose-dependent fashion: 0.1 nM, 10 nM and 1000 nM ANG II increased NO-oxidation current by 85+/-18 pA (n = 11), 148+/-22 pA (n = 11), and 193+/-29 pA (n = 11), respectively. These currents correspond to changes in effluent NO concentration of 3.4+/-0.5 nM, 6.1+/-1.1 nM, and 8.2+/-1.3 nM, respectively. Neither LOS (1 muM) nor CAN (1 nM) significantly affected basal NO production, but both AT1-receptor blockers markedly blunted NO release in response to ANG II (10 nM): 77+/-6% inhibition with LOS (n = 8) and 63+/-9% with CAN (n = 8). These results are the first to demonstrate that ANG II stimulates NO release in isolated renal resistance arteries, and that ANG II-induced NO release is blunted by simultaneous AT1-receptor blockade. Our findings suggest that endothelium-dependent modulation of ANG II-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1-receptor-dependent NO release.     

BRCA1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA1

Mutations in the BRCA1/BRCA2 genes account for varying proportions of breast cancer families studied, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations in 17 families from Wales with two or more cases of breast cancer under age 50 and/or ovarian cancer. Eight out of 17 (47%) families had demonstrable mutations. Six out of 17 (35%) carried BRCA1 mutations and 2 out of 17 (12%) carried BRCA2 mutations. Two recurrent mutations in BRCA1 were identified, which appear to represent founder mutations in this population. These data support the existence of additional breast and ovarian cancer susceptibility genes.     

Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.     

BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease

Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.     

Cancer risk among women with cosmetic breast implants: a population-based cohort study in Sweden

Complementary DNAs encoding the heavy and light chains of the Fab fragment of mouse agglutinating monoclonal antibody against human red blood cells were cloned by polymerase chain reaction and their nucleotide sequences were determined. The sequence analysis showed that the variable regions of the heavy and light chains were the members of mouse heavy-chain subgroup IIa and kappa light-chain subgroup I, respectively. A few unusual amino acids in the constant regions of the heavy chain were also recognized.     

Gender differences in physical aggression: A prospective population-based survey of children before and after 2 years of age.

There has been much controversy over the past decades on the origins of gender differences in children's aggressive behavior. A widely held view is that gender differences emerge sometime after 2 years of age and increase in magnitude thereafter because of gender-differentiated socialization practices. The objective of this study was to test for (a) gender differences in the prevalence of physical aggression in the general population of 17-month-old children and (b) change in the magnitude of these differences between 17 and 29 months of age. Contrary to the differential socialization hypothesis, the results showed substantial gender differences in the prevalence of physical aggression at 17 months of age, with 5% of boys but only 1% of girls manifesting physically aggressive behaviors on a frequent basis. The results suggest that there is no change in the magnitude of these differences between 17 and 29 months of age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk

PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.     

Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes?

To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene.     

Pregnancies of women with epilepsy: a population-based study in Iceland

PURPOSE: Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered to have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection. METHODS: We performed a historical population-based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19-year period in Iceland. RESULTS: In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7-fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy. CONCLUSIONS: Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring.     

The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases

Cowden syndrome (CS) is an autosomal dominant disorder associated with the development of hamartomas and benign tumors in a variety of tissues, including the skin, thyroid, breast, endometrium, and brain. It has been suggested that women with CS are at increased risk for breast cancer. A locus for CS was recently defined on chromosome 10 in 12 families, resulting in the identification of the CS critical interval, between the markers D10S215 and D10S541. More recently, affected individuals in four families with CS have been shown to have germ-line mutations in a gene known as "PTEN," or "MMAC1," which is located in the CS critical interval on chromosome 10. In this study, we report three novel MMAC1 mutations in CS and demonstrate that MMAC1 mutations are associated with CS and breast cancer. Furthermore, we also show that certain families and individuals with CS do not have mutations in the coding sequence of MMAC1. Finally, we did not detect MMAC1 mutations in a subpopulation of individuals with early-onset breast cancer, suggesting that germ-line mutations in this gene do not appear to be common in this group.     

The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women

The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations.     

Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes

The World Health Organization criteria for the diagnosis of Osteopenia and Osteopoposis was applied to a control group of 33 females ages 50 to 59 years and 24 females ages 60 to 69 years. The general exclusion criteria for the selection of subjects included early menopause and diseases, use of drugs and toxic habits such as smoking and alcoholism, known to affect bone and mineral metabolism. Bone mineral densities were measured with a DEXA Hologic, model 1000. In the reference population mean peak bone mineral density expressed in g/cm2 was 1.051 (SD = 0.119) for the lumbar spine at age 30 to 39 years and for the femoral neck 0.861 (SD = 0.098) at age 20 to 29 years. Bone densities below 1 to 2.5 SD from mean peak bone mass ranged from 0.932 to 0.754 g/cm2 in the lumbar spine and 0.763 to 0.616 g/cm2 for the femoral neck. The mean age of the pooled group was 58.4 years. The prevalence of osteopenia in the pooled group was 42 % for the lumbar spine and 56% for the femoral neck and of osteoporosis, 12% for the lumbar spine and 8.7% for the femoral neck. A similar prevalence has been found by other investigators in hispanic populations. Such a high percentage of females with osteopenia implicates that bone densitometry must be done in the perimenopausal years and in young individuals at risk so as to proceed with early medical intervention to prevent osteoporosis.     

Dietary fat, calories, and the risk of breast cancer in postmenopausal women: a prospective population-based study

We tested the hypothesis that a high-fat diet increases the risk of breast cancer in a population-based study of 590 women aged 40-79 years who were without known breast cancer when they provided a quantitative 24-hour diet recall. Fifteen postmenopausal women were diagnosed with incident breast cancer during the next 15 years (approximately 7600 person-years of follow-up). These women had significantly higher age-adjusted intake of all fats (monounsaturated, polyunsaturated, and saturated), and oleic, linoleic, and linolenic acids, with a stepwise increase in risk across tertiles of intake. Fat intake was associated with total calories, protein, and carbohydrates, and women with incident breast cancer consumed more calories, protein, and carbohydrates than did other subjects. When each nutrient variable (calories, fats, protein, and carbohydrates) was adjusted for age, body mass index, age at menopause, parity, and alcohol consumption, the strongest risks for incident breast cancer were associated with total calories (relative risk per standard deviation = 2.72, 95% confidence interval = 1.51-4.89, p = 0.002) and total fats (relative risk per standard deviation = 2.01, 95% confidence interval = 1.19-3.41, p = 0.01). Fat composition of the diet, expressed either as percent of energy or as fat intake adjusted for calories by regression analysis, was not significantly associated with risk of breast cancer. These results support the hypothesis that total calorie consumption, as well as dietary fat consumption, is a risk factor for breast cancer in postmenopausal women, and parallel observations in animal models.     

Thyroid functions and serum lipids in older women: a population-based study

A new allelic series at the underwhite gene is described. Three of the alleles in the series--uw, uwd, and Uwdbr--arose as spontaneous mutations on different genetic backgrounds at The Jackson Laboratory. We report here the visible phenotypes and dominance hierarchy of these alleles, all of which are defined by a reduction of pigmentation in both eye and coat color. Electron microscopic analysis of retinal epithelium suggests that the primary defect is in the melanosome. The degree of severity of melanosome anomalies in the retina correlates with the degree of hypopigmentation in the coat. The perturbed gene and its gene product are unknown. We show that the uw locus is genetically distinct from Myo10, a suggested candidate gene for this mutation.