| 1. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 2. |
- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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| 3. |
- Lagerström, Robert, 1981-, et al.
(författare)
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A Methodology for Operationalizing Enterprise IT Architecture and Evaluating its Modifiability
- 2019
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Ingår i: Complex Systems Informatics and Modeling Quarterly. - : Riga Technical University. - 2255-9922. ; 19, s. 75-98
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Tidskriftsartikel (refereegranskat)abstract
- Recent contributions to information systems theory suggest that the primary role of a firm’s information technology (IT) architecture is to facilitate, and therefore ensure the continued alignment of a firm’s IT investments with a constantly changing business environment. Despite the advances we lack robust methods with which to operationalize enterprise IT architecture, in a way that allows us to analyze performance, in terms of the ability to adapt and evolve over time. We develop a methodology for analyzing enterprise IT architecture based on “Design Structure Matrices” (DSMs), which capture the coupling between all components in the architecture. Our method addresses the limitations of prior work, in that it i) captures the architecture “in-use” as opposed to high level plans or conceptual models; ii) identifies discrete layers in the architecture associated with different technologies; iii) reveals the “flow of control” within the architecture; and iv) generates measures that can be used to analyze performance. We apply our methodology to a dataset from a large pharmaceutical firm. We show that measures of coupling derived from an IT architecture DSM predict IT modifiability – defined as the cost to change software applications. Specifically, applications that are tightly coupled cost significantly more to change.
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| 4. |
- Lagerström, Robert, 1981-, et al.
(författare)
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Visualizing and Measuring Enterprise Architecture : An Exploratory BioPharma Case
- 2013
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Ingår i: The 6<sup>th</sup> IFIP WG 8.1 Working Conference on the Practice of Enterprise Modeling (PoEM). - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783642416408 ; , s. 9-23
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Konferensbidrag (refereegranskat)abstract
- We test a method for visualizing and measuring enterprise application architectures. The method was designed and previously used to reveal the hidden internal architectural structure of software applications. The focus of this paper is to test if it can also uncover new facts about the applications and their relationships in an enterprise architecture, i.e., if the method can reveal the hidden external structure between software applications. Our test uses data from a large international telecom company. In total, we analyzed 103 applications and 243 dependencies. Results show that the enterprise application structure can be classified as a core-periphery architecture with a propagation cost of 25%, core size of 34%, and architecture flow through of 64%. These findings suggest that the method could be effective in uncovering the hidden structure of an enterprise application architecture.
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| 5. |
- Lagerström, Robert, 1981-, et al.
(författare)
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Visualizing and Measuring Software Portfolio Architecture : A Flexibility Analysis
- 2014
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Ingår i: 16th International Dependency and Structure Modelling Conference, DSM 2014. - München : Carl Hanser Verlag GmbH & Co. KG. ; , s. 65-74
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Konferensbidrag (refereegranskat)abstract
- In this paper, we test a Design Structure Matrix (DSM) based method for visualizing and measuring software portfolio architectures, and use our measures to predict the costs of architectural change. Our data is drawn from a biopharmaceutical company, comprising 407 architectural components with 1,157 dependencies between them. We show that the architecture of this system can be classified as a "core-periphery" system, meaning it contains a single large dominant cluster of interconnected components (the "Core") representing 32% of the system. We find that the classification of software applications within this architecture, as being either Core or Peripheral, is a significant predictor of the costs of architectural change. In regression tests, we show that this measure has greater predictive power than prior measures of coupling used in the literature.
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