Simulating full-sky interferometric observations

Aperture array interferometers, such as that proposed for the Square Kilometre Array (SKA), will see the entire sky, hence the standard approach to simulating visibilities will not be applicable since it relies on a tangent plane approximation that is valid only for small fields of view. We derive interferometric formulations in real, spherical harmonic and wavelet space that include contributions over the entire sky and do not rely on any tangent plane approximations. A fast wavelet method is developed to simulate the visibilities observed by an interferometer in the full-sky setting. Computing visibilities using the fast wavelet method adapts to the sparse representation of the primary beam and sky intensity in the wavelet basis. Consequently, the fast wavelet method exhibits superior computational complexity to the real and spherical harmonic space methods and may be performed at substantially lower computational cost, while introducing only negligible error to simulated visibilities. Low-resolution interferometric observations are simulated using all of the methods to compare their performance, demonstrating that the fast wavelet method is approximately three times faster that the other methods for these low-resolution simulations. The computational burden of the real and spherical harmonic space methods renders these techniques computationally infeasible for higher resolution simulations. High-resolution interferometric observations are simulated using the fast wavelet method only, demonstrating and validating the application of this method to realistic simulations. The fast wavelet method is estimated to provide a greater than ten-fold reduction in execution time compared to the other methods for these high-resolution simulations.Comment: 16 pages, 9 figures, replaced to match version accepted by MNRAS (major additions to previous version including new fast wavelet method

Mutation analysis of the MDM4 gene in German breast cancer patients

<p>Abstract</p> <p>Background</p> <p>MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, however, whether <it>MDM4 </it>gene alterations play some role in the inherited component of breast cancer susceptibility.</p> <p>Methods</p> <p>We sequenced the whole <it>MDM4 </it>coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls.</p> <p>Results</p> <p>Our resequencing study uncovered two <it>MDM4 </it>coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened.</p> <p>Conclusion</p> <p>This study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of <it>MDM4 </it>coding variants in the inherited susceptibility towards breast cancer in German patients.</p

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.</p> <p>Methods</p> <p>In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the <it>NBN </it>gene in our cohort of 97 high-risk non-<it>BRCA1 </it>and -<it>BRCA2 </it>breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. <it>In silico </it>programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.</p> <p>Results</p> <p>Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.</p> <p>Conclusion</p> <p>Our analysis of <it>NBN </it>sequence variations indicated that potential <it>NBN </it>alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in <it>NBN </it>promoter region.</p

Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke