Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2 kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.co

A Review of the Intrinsic Heavy Quark Content of the Nucleon

We present a review of the state of the art of our understanding of the intrinsic charm and bottom content of the nucleon. We discuss theoretical calculations, constraints from global analyses, and collider observables sensitive to the intrinsic heavy quark distributions. A particular emphasis is put on the potential of a high energy and high luminosity fixed target experiment using the LHC beams (AFTER@LHC) to search for intrinsic charm

Enhanced magnetic moment and conductive behavior in NiFe2O4 spinel ultrathin films

Bulk NiFe2O4 is an insulating ferrimagnet. Here, we report on the epitaxial growth of spinel NiFe2O4 ultrathin films onto SrTiO3 single-crystals. We will show that - under appropriate growth conditions - epitaxial stabilization leads to the formation of a spinel phase with magnetic and electrical properties that radically differ from those of the bulk material : an enhanced magnetic moment (Ms) - about 250% larger - and a metallic character. A systematic study of the thickness dependence of Ms allows to conclude that its enhanced value is due to an anomalous distribution of the Fe and Ni cations among the A and B sites of the spinel structure resulting from the off-equilibrium growth conditions and to interface effects. The relevance of these findings for spinel- and, more generally, oxide-based heterostructures is discussed. We will argue that this novel material could be an alternative ferromagetic-metallic electrode in magnetic tunnel junctions.Comment: accepted for publication in Phys. Rev.

Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer.

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families

Vacuum stability and perturbativity of SU(3) scalars

We calculate the vacuum stability conditions and renormalisation group equations for the extensions of standard model with a higher colour multiplet scalar up to the representation 1 5 0 that leaves the strong interaction asymptotically free. In order to find the vacuum stability conditions, we calculate the orbit spaces for the self-couplings of the higher multiplets, which for the representations 1 5 and 1 5 0 of SU(3)(c) are highly complicated. However, if the scalar potential is linear in orbit space variables, it is sufficient to know the convex hull of the orbit space. Knowledge of the orbit spaces also facilitates the minimisation of the potentials. In contrast to the self-couplings of other multiplets, we find that the scalar quartic couplings of the representations 3 and 8 walk rather than run, remaining nearly constant and perturbative over a vast energy range. We describe the conditions for walking couplings using a schematic model. With these technical results at hand we revise earlier results of generation of new scales with large SU(3) c scalar multiplets. Our results are easily extendable to models of new physics with additional SU(3) or SU(N) gauge symmetries.Peer reviewe

Ethical, social and economic issues in familial breast cancer: a compilation of views from the EC biomed II demonstration project

ABSTRACT: Demand for clinical services for familial breast cancer is continuing to rise across Europe. Service provision is far from uniform and, in most centres, its evolution has been determined by local conditions, specifically by local research interests, rather than by central planning. However, in a number of countries there is evidence of progress towards co-ordinated development and audit of clinics providing risk assessment, counselling, screening and, in some cases, prophylactic intervention. Much important information should emerge from continued observation and comparative assessment of these developments. In most countries for which relevant data are available, there is a distinct bias towards higher social class among those who avail themselves of clinic facilities (in line with findings from many other health-promotion initiatives). This should be addressed when considering future organisation of clinical services. Molecular genetic studies designed to identify the underlying mutations responsible for familial breast cancer are not generally regarded as part of the clinical service and are funded through research grants (if at all). Economic considerations suggest that there is a case for keeping this policy under review. Familial cancers throw into sharp relief certain ethical and legal issues that have received much recent attention from government advisory bodies, patients ’ representatives, professional commentators and the popular media. Two are of particular importance; first, the right to gain access to medical records of relatives, in order to provide accurate risk assessment for a given family member, versus the right to privacy in respect of personal medical information and, second, the obligation (or otherwise) to inform family members of their risk status if they have not actively sought that knowledge. The legal position seems to vary from country to country and, in many cases, is unclear. In view of pressures to establish uniform approaches to medical confidentiality across the EC, it is important to evaluate the experience of participants in this Demonstration Programme and to apply the principle of “ non-malfeasance ” in formulating regu- lations that should govern future practice in this field. Data on economic aspects of familial breast cancer are remarkably sparse and outdated. As evidence accrues on the influence of screening and intervention programmes on morbidity and mortality, there is a strong case for evaluating the cost-effectiveness of different models of service provisi

Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence.

Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation