Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Common germline polymorphisms associated with breast cancer-specific survival

Abstract Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels

Test-Driven Development pada Pengembangan Aplikasi Android untuk Memantau COVID-19

Dalam pengembangan perangkat lunak, terdapat banyak teknik dan pendekatan yang digunakan untuk menghasilkan perangkat lunak yang handal. Kualitas perangkat lunak sangat bergantung pada pengujian perangkat lunak. Namun tidak semua pengembang peduli dengan tahapan pengujian pada sebuah perangkat lunak. Penelitian ini bertujuan untuk mengetahui pengaruh dari menerapkan proses pengujian dalam mengembangkan perangkat lunak dengan menggunakan metode TDD. Pada Metode TDD, pengembangan perangkat lunak dimulai dengan menulis test case terlebih dahulu lalu kemudian menulis kode. Pada artikel ini, dikembangkan aplikasi mobile dengan menerapkan metode TDD. Perangkat lunak yang dikembangkan adalah berupa sistem informasi mengenai data laporan kasus COVID-19. Data diambil dari Johns Hopkins University The Center of Systems Science and Engineering (JHU CSSE). Hasil penerapan metode TDD menunjukkan bahwa fungsi dan fitur dari perangkat lunak yang dibangun dapat bekerja dan terintegrasi dengan baik antar satu sama lain. Kode yang dihasilkan dari penerapan TDD juga menjadi rapih karena dilakukannya proses refactoring. In Software Engineering, there are many techniques and approaches that can be used to build a reliable software. The quality of a software relies mostly on the software testing process. However, not many developers are bothered with the testing step of a software. The purpose of this article is to learn the results from implementing a testing process on software developmenty. In TDD, the development is started by writing test case first and then writing code. This article developed a mobile application by applying TDD in the process. The android application that had been developed is an information system about report cases on COVID-19. The cases are coming from Johns Hopkins University The Center of Systems Science and Engineering (JHU CSSE). The result of using TDD in development proves that all functions and features of the developed application are working and integrated well

Plant reproduction in the alpine landscape : reproductive ecology, genetic diversity and gene flow of the rare monocarpic "Campanula thyrsoides" in the Swiss Alps

Aims & Objectives The work presented in this thesis forms part of a larger project “How patchy habitat and isolation affect alpine plant life: genetic diversity, gene flow and mating systems”, which includes the PhD studies of Patrick Kuss and the author under the supervision of Professor Jürg Stöcklin. This doctoral thesis investigates the consequences of the natural fragmentation and patchiness of alpine landscapes on the life of alpine plant populations. The central focus of the thesis is on the mating system, the role of inbreeding and/or outbreeding depression, genetic diversity and geographic structure within and among populations of the rare Alpine monocarpic perennial Campanula thyrsoides. The main objectives and research questions addressed are: • Is Campanula thyrsoides self-compatible (SI) and if not, does the SI system break down with flower age? Do inbred C. thyrsoides offspring in the common garden suffer from inbreeding depression? • Do we find a distance related inbreeding depression (poorer reproducive output) or outbreeding depression (increased reproductive output) in field populations of C. thyrsoides following crosses of different crossing distances (selfing, 1m, 10m, 100m and among distant populations)? • How much genetic diversity exists within populations of C. thyrsoides and how does it relate to population size and altitude? Has the natural habitat fragmentation let to strong genetic differentiation and restricted gene flow among populations of C. thyrsoides resulting in a pronounced geographic structure? Study species In order to seek answers to our research questions, we choose to study a yellow bellflower; Campanula thyrsoides. The choice was based on the information that C. thyrsoides is a rare plant species, which is only found on calcarious soils within the European Alps and adjacent mountain ranges (Aeschimann et al. 2005). The plants selectiveness for carbonate bearing soils together with the fact that its seeds are not adapted to long-distance dispersal (Tackenberg 2003) are the main reasons for the isolation and small sizes of many of its populations. These population characteristics, therefore, made C. thyrsoides a suitable study species. Another important characteristic of C. thyrsoides, and one of the main reasons for its inclusion in the study is because it is a monocarpic perennial which flowers once and subsequently dies (Jäger 2000). Monocarpic plants species, which are more commonly found in subtropical and tropical mountain systems (e.g. the giant rosettes of Puya spp, Espeletia spp., Echium spp. etc., Smith & Young 1987; Young & Augspurger 1991) are rare amidst the temperate alpine flora (for the Alps, see Aeschimann et al. 2005). Monocarpy can promote genetic differentiation between populations by reducing the effective population size due to a shorter generation time and lower density of populations (Loveless & Hamrick 1984; Vitalis et al. 2004). When studying the effects of population isolation and habitat fragmentation on plant reproduction (e.g. mating system and inbreeding depression), it is, moreover, ideal to study a Campanula species. Although most Campanula species are selfincompatible and allogamous (Nyman 1993), both a break-down in the SI system with flower age (Vogler et al. 1998) and an evolution towards complete self-compatibility (Ægisdóttir & Thórhallsdóttir 2006) have been recorded. Design We studied the reproductive ecology and genetic diversity of Campanula thyrsoides by firstly setting up pollination experiments in the common garden and in the field and secondly by sampling leaf material in 32 field populations in Switzerland. In the common garden study, we set up a pollination experiment in order to study the breeding system of C. thyrsoides, including the consequences of selfing, half-sibling crossings and outcrossing on reproductive output and seedling performance. Moreover, field experiments in four populations were set up in the Swiss Alps in order to study the effect of different crossing distances on reproduction in C. thyrsoides and to see if evidence would be found of hidden inbreeding depression or outbreeding depression following large-distance crossings compared to within-population crossings. In addition, we studied the genetic diversity, gene flow and geographical structure within and among 32 field populations of C. thyrsoides in Switzerland, covering both large geographical and altitudinal ranges. The genetic study was conducted using 5 co-dominant microsatellite markers. In addition, we studied the genetic diversity in C. thyrsoides and two other alpine plants using random amplified polymorphic DNA (RAPD) marker as well as studing the evolutionary demography of C. thyrsoides

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology