611 research outputs found
Founder populations and their uses for breast cancer genetics
Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation, allowing for a more rapid and less expensive test. In addition, more precise estimates of the prior probability of carrying a mutation and of the likelihood of a mutation carrier developing cancer should be possible. For a given founder mutation a large number of carriers are available, so that focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk can be performed. Finally, founder populations may be a powerful resource to localize additional breast cancer susceptibility loci, because of the reduction in locus heterogeneity
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Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression
The f_LT Response Function of D(e,e'p)n at Q^2=0.33(GeV/c)^2
The interference response function f_LT (R_LT) of the D(e,e'p)n reaction has
been determined at squared four-momentum transfer Q^2 = 0.33 (GeV/c)^2 and for
missing momenta up to p_miss= 0.29 (GeV/c). The results have been compared to
calculations that reproduce f_LT quite well but overestimate the cross sections
by 10 - 20% for missing momenta between 0.1 (GeV/c) and 0.2 (GeV/c) .Comment: 12 Pages, 10 figure
New detectors for the kaon and hypernuclear experiments with KaoS at MAMI and with PANDA at GSI
The KaoS spectrometer at the Mainz Microtron MAMI, Germany, is perceived as
the ideal candidate for a dedicated spectrometer in kaon and hypernuclei
electroproduction. KaoS will be equipped with new read-out electronics, a
completely new focal plane detector package consisting of scintillating fibres,
and a new trigger system. First prototypes of the fibre detectors and the
associated new front-end electronics are shown in this contribution. The Mainz
hypernuclei research program will complement the hypernuclear experiments at
the planned FAIR facility at GSI, Germany. At the proposed antiproton storage
ring the spectroscopy of double Lambda hypernuclei is one of the four main
topics which will be addressed by the PANDA Collaboration. The experiments
require the operation of high purity germanium (HPGe) detectors in high
magnetic fields (B= 1T) in the presence of a large hadronic background. The
performance of high resolution Ge detectors in such an environment has been
investigated.Comment: Presentation at International Symposium on the Development of
Detectors for Particle, Astroparticle and Synchrotron Radiation Experiments,
Stanford, Ca (SNIC06), 6 pages, LaTeX, 11 eps figure
A measurement of the axial form factor of the nucleon by the p(e,e'pi+)n reaction at W=1125 MeV
The reaction p(e,e'pi+)n was measured at the Mainz Microtron MAMI at an
invariant mass of W=1125 MeV and four-momentum transfers of Q^2=0.117, 0.195
and 0.273 (GeV/c)^2. For each value of Q^2, a Rosenbluth separation of the
transverse and longitudinal cross sections was performed. An effective
Lagrangian model was used to extract the `axial mass' from experimental data.
We find a value of M_A=(1.077+-0.039) GeV which is (0.051+-0.044) GeV larger
than the axial mass known from neutrino scattering experiments. This is
consistent with recent calculations in chiral perturbation theory.Comment: 14 pages, 5 figures, uses elsart.cl
Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB
Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
Peer reviewedPublisher PD
Precise Neutron Magnetic Form Factors
Precise data on the neutron magnetic form factor G_{mn} have been obtained
with measurements of the ratio of cross sections of D(e,e'n) and D(e,e'p) up to
momentum transfers of Q^2 = 0.9 (GeV/c)^2. Data with typical uncertainties of
1.5% are presented. These data allow for the first time to extract a precise
value of the magnetic radius of the neutron.Comment: 10 pages, 2 figures, submitted to Physics Letters
Measurement of Rlt and Atl in the 4He(e,e'p)3H Reaction at pmiss of 130-300 MeV/c
We have measured the 4He(e,e'p)3H reaction at missing momenta of 130-300
MeV/c using the three-spectrometer facility at the Mainz microtron MAMI. Data
were taken in perpendicular kinematics to allow us to determine the response
function Rlt and the asymmetry term Atl. The data are compared to both
relativistic and non-relativistic calculations.Comment: To be published in the European Physical Journal
Rapid detection of carriers with BRCA1 and BRCA2 mutations using high resolution melting analysis
<p>Abstract</p> <p>Background</p> <p>Germline inactivating mutations in <it>BRCA1 </it>and <it>BRCA2 </it>underlie a major proportion of the inherited predisposition to breast and ovarian cancer. These mutations are usually detected by DNA sequencing. Cost-effective and rapid methods to screen for these mutations would enable the extension of mutation testing to a broader population. High resolution melting (HRM) analysis is a rapid screening methodology with very low false negative rates. We therefore evaluated the use of HRM as a mutation scanning tool using, as a proof of principle, the three recurrent BRCA1 and BRCA2 founder mutations in the Ashkenazi Jewish population in addition to other mutations that occur in the same regions.</p> <p>Methods</p> <p>We designed PCR amplicons for HRM scanning of <it>BRCA1 </it>exons 2 and 20 (carrying the founder mutations185delAG and 5382insC respectively) and the part of the <it>BRCA2 </it>exon 11 carrying the 6174delT founder mutation. The analysis was performed on an HRM-enabled real time PCR machine.</p> <p>Results</p> <p>We tested DNA from the peripheral blood of 29 individuals heterozygous for known mutations. All the Ashkenazi founder mutations were readily identified. Other mutations in each region that were also readily detected included the recently identified Greek founder mutation 5331G>A in exon 20 of <it>BRCA1</it>. Each mutation had a reproducible melting profile.</p> <p>Conclusion</p> <p>HRM is a simple and rapid scanning method for known and unknown <it>BRCA1 </it>and <it>BRCA2 </it>germline mutations that can dramatically reduce the amount of sequencing required and reduce the turnaround time for mutation screening and testing. In some cases, such as tracking mutations through pedigrees, sequencing may only be necessary to confirm positive results. This methodology will allow for the economical screening of founder mutations not only in people of Ashkenazi Jewish ancestry but also in other populations with founder mutations such as Central and Eastern Europeans (<it>BRCA1 </it>5382insC) and Greek Europeans (<it>BRCA1 </it>5331G>A).</p
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