Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families

Serum samples from 47 men with current condylomas, 32 men with a history of condylomas and from 205 men with no history of genital wart disease, who were attending sexually transmitted disease (STD) clinics at two different hospitals in Stockholm, were analyzed for the presence of immunoglobulin G (IgG) and A (IgA) antibodies to capsids of human papillomavirus types 6 and 11. IgG to HPV type 6 was found among 35% of patients with a history of condylomas compared to 10% of controls (p = 0.0003), but only among 27% of patients with current condylomas. Antibodies to HPV 6 and to HPV 11 showed a very limited correlation, suggesting that the antibodies are HPV-type restricted. The results strengthen conclusions from a previous serological study indicating that IgG antibodies against HPV 6 develop late during condylomatous disease and mostly reflect previous exposure to the virus.     

A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families

We have identified 79 mutations in BRCA1 in a set of 643 Dutch and 23 Belgian hereditary breast and ovarian cancer families collected either for research or for clinical diagnostic purposes. Twenty-eight distinct mutations have been observed, 18 of them not previously reported and 12 of them occurring more than once. Most conspicuously, a 2804delAA mutation has been found 19 times and has never been reported outside the Netherlands. A common haplotype spanning > or = 375 kb could be identified for each of the nine examined recurrent mutations, indicating the presence of multiple BRCA1 founder mutations in the Dutch population. The 2804delAA mutation has been estimated to have originated approximately 32 generations ago. No specific breast or ovarian cancer phenotype could be assigned to any of the common mutations, and the ovarian cancer incidence among 18 families with the 2804delAA mutation was heterogeneous.     

BRCA2 germline mutations in Swedish breast cancer families

Life-threatening situations in sarcoidosis are extremely rare. They may be due to failure of vital organs--lungs, heart, kidney, liver and brain--and usually due to irreversible fibrosis. Respiratory failure follows irreversible pulmonary fibrosis and the development of cor pulmonale. Cardiac sarcoidosis is more sinister for it may be silent, ill-recognised with sudden death or high morbidity. It needs sophisticated techniques to uncover this latent iceberg. Renal failure may be due to granulomatous interstitial nephritis and/or nephrocalcinosis. Hepatic failure is due to intrahepatic cholestasis, portal hypertension and bleeding oesophageal varices. Neurosarcoidosis carries a mortality of 10 per cent, over twice that of sarcoidosis overall. The treatment of each situation is discussed including organ transplantation.     

Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer

The BRCA1 gene on human chromosome 17q21 is responsible for an autosomal dominant syndrome of inherited early onset breast/ovarian cancer. It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer. The BRCA1 gene has recently been isolated and mutations have been found in the germline of affected individuals in linked families. Previous studies of loss of heterozygosity (LOH) in breast tumors have been carried out on sporadic tumors derived from individuals without known linkage to BRCA1 and on tumors from linked families. Loss of large regions of chromosome 17 has been observed, but these LOH events could not be unequivocally ascribed to BRCA1. We have studied 28 breast and 6 ovarian tumors from families with strong evidence for linkage between breast cancer and genetic markers flanking BRCA1. These tumors were examined for LOH using genetic markers flanking and within BRCA1, including THRA1, D17S856, EDH17B1, EDH17B2, and D17S183. Forty-six percent (16/34) of tumors exhibit LOH which includes BRCA1. In 8 of 16 tumors the parental origin of the deleted allele could be determined by evaluation of haplotypes of associated family members; in 100% of these cases, the wild-type allele was lost. In some of these families germline mutations in BRCA1 have been determined; analyses of tumors with LOH at BRCA1 have revealed that only the disease-related allele of BRCA1 was present. These data strongly support the hypothesis that BRCA1 is a tumor suppressor gene.     

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.     

Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families

Germ-line BRCA1 and BRCA2 mutations account for most of familial breast-ovarian cancer. In Ashkenazi Jews, there is a high population frequency (approximately 2%) of three founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. This study examined the frequency of these mutations in a series of Ashkenazi women with ovarian cancer unselected for family history, compared with the frequency of these mutations in families ascertained on the basis of family history of at least two affected women. Penetrance was compared, both according to the method of family ascertainment (i.e., on the basis of an unselected ovarian cancer proband vs. on the basis of family history) and for the BRCA1 founder mutations compared with the BRCA2 6174delT mutation. There was a high frequency (10/22; [45%]) of germ-line mutations in Ashkenazi women with ovarian cancer, even in those with minimal or no family history (7/18 [39%]). In high-risk Ashkenazi families, a founder mutation was found in 59% (25/42). Families with any case of ovarian cancer were significantly more likely to segregate a founder mutation than were families with site-specific breast cancer. Penetrance was higher in families ascertained on the basis of family history than in families ascertained on the basis of an unselected proband, but this difference was not significant. Penetrance of BRCA1 185delAG and BRCA1 5382insC was significantly higher than penetrance of BRCA2 6174delT (hazard ratio 2.1 [95% CI 1.2-3.8]; two-tailed P = .01). Thus, the high rate of germ-line BRCA1/BRCA2 mutations in Ashkenazi women and families with ovarian cancer is coupled with penetrance that is lower than previously estimated. This has been shown specifically for the BRCA2 6174delT mutation, but, because of ascertainment bias, it also may be true for BRCA1 mutations.     

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.     

Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1

BACKGROUND: Stentless aortic xenografts are an important addition to the range of prosthetic valves. So far their use has been restricted to a limited number of study centers. This report summarizes the principal findings from the Second International Symposium on Stentless Bioprostheses. Attention is focused on the Toronto SPV and Freestyle valves recently approved by the United States Food and Drug Administration. METHODS: Stentless xenografts are used predominantly in elderly patients with aortic stenosis. Implant techniques are more complex than for stented valves, as reflected by longer ischemic and cardiopulmonary bypass times. The valves have been subjected to detailed serial echocardiographic assessment and clinical follow-up. RESULTS: The hemodynamic characteristics resemble those of the aortic homograft. There is a progressive increase in effective orifice area and decrease in transvalvular pressure gradients with time. Left ventricular mass index and wall thickness normalize between 6 and 12 months postoperatively. Left ventricular remodeling is accompanied by improved symptomatic status and a low incidence of valve-related complications. Limited comparative studies suggest important benefits over stented xenografts. Improved hemodynamics may translate into better bioprosthetic durability. CONCLUSIONS: Reproducible and reliable implant methods should be taught carefully, but the hemodynamic advantages are substantial. Stentless xenografts are ideal for the elderly patient with aortic stenosis.     

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.     

Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer

Bone loss after oophorectomy of adult rats is more rapid and complete in the metaphysis than in the epiphysis of the femur, particularly in the proximal region of the metaphysis distant from the growth plate. This study was undertaken to determine the effects of prepubertal oophorectomy, on femoral cancellous bone acquisition during growth. Rats were oophorectomized (OVX) or sham operated at 3 weeks of age and killed at intervals up to 78 weeks for scanning electron microscopy and histomorphometry of the distal femur. Differences in cancellous bone architecture between the two groups was evident after 6 weeks of age. Relatively minor differences were found in the part of the metaphysis near the growth plate and in the epiphysis, with less trabeculae in the primary spongiosa and 1 to 2 less trabeculae/mm in the secondary spongiosa. However, as metaphyseal growth proceeded, trabeculae were present for a greater distance up the femoral shaft in controls than in OVX rats, with mean BV/TV in the proximal part of the metaphysis increasing from 1.4% at 6 weeks to 13.4% at 20 weeks in controls, with no increase in the OVX rats. We find that the lack of ovarian hormones increases the rate of destruction of trabeculae near the metaphyseal-diaphyseal junction.     

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.     

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.     

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.     

The BRCA1 and BRCA2 breast cancer genes

This review discusses the need for sleep, effects of sleep deprivation on behaviour and performance in the military, and sleep management recommendations to optimise combat effectiveness. Most people, regardless of sex or race, prefer 7 to 8 hours of sleep each night. Sleeping during the day is less recuperative. Continuous sleep is more effective than multiple short naps-even when the total hours for naps is more. Ten to 20 minute naps are useful when continuous sleep is not possible. Sleep inertia is the 5 to 30 minute period of sluggishness after awakening and important military tasks should be avoided. Previously, continuous work episodes (CWEs) duration was restricted by limited night vision, unreliable equipment and reduced endurance of military personnel. With improved technology, CWEs are now restricted primarily by endurance which is affected by sleep deprivation. This was one of the experiences noted in recent conflicts (e.g. Desert Storm) by personnel in the air force, army and navy. Since there will be changes in operational requirements, several work-rest-sleep plans must be prepared. Sleeping the preferred 7 to 8 hours per 24 hours the week before an operation may help prepare for optimal performance. Personnel should be familiarised with conditions under which they may sleep. During combat, sleep management should ideally avoid situations where all personnel are exhausted at the same time. As sleep debt accumulates, a person's mood, motivation, attention, alertness, short-term memory, ability to complete routines, task performance (errors of omission more than errors of commission) and physical performance will become more negatively affected. Counter measures must then be taken (e.g. time for sleep or naps, changing routines or rotating jobs). Drugs like caffeine and amphetamine can help personnel stay awake. However, they may also keep them awake when they need to sleep- and on awakening, they could suffer from "hang-overs" and are less efficient. Sleep lost need not be replaced hour-for-hour. Therefore, after operations, personnel need continuous sleep for only 10 to 12 hours as longer sleep increases sleep inertia and delays getting back to normal schedules.     

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)