| 1. |
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| 2. |
- Kainu, T, et al.
(author)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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In: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Journal article (peer-reviewed)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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| 3. |
- Lieu Tran, T. B., et al.
(author)
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Trends in preparing cyber-physical systems engineers
- 2019
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In: Cyber-Physical Systems. - : Taylor and Francis Ltd.. - 2333-5785 .- 2333-5777. ; 5:2, s. 65-91
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Journal article (peer-reviewed)abstract
- Demand for prepared Cyber-physical systems (CPSs) engineers is growing in the Industry 4.0 economy and universities should respond accordingly. This article identifies trends in preparing the CPSs workforce of the future by reviewing educational curricula and research on CPSs of universities around the world. The research finds three main approaches being deployed: 1) Offering universal CPSs foundational training for different industrial fields; 2) becoming more focus on CPSs training at the doctoral level and for a specific industrial field; and 3) CPSs training as an embedded or introduction course in engineering curricula. The research identifies a need for ‘educational renewal’ in the era of CPSs training. Reorganizing university structures for collaboration and innovation in CPSs training and research is essential. Preparing interdisciplinary CPSs doctoral-level graduates and engineers for specific industrial fields should become a central focus. Equipping CPSs engineers with skills, especially creativity and entrepreneurial competencies, should be a priority.
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| 4. |
- Alelyani, T., et al.
(author)
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A literature review on obsolescence management in COTS-centric cyber physical systems
- 2019
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In: Procedia Computer Science. - : Elsevier B.V.. - 1877-0509. ; , s. 135-145
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Conference paper (peer-reviewed)abstract
- Commercial off-the-shelf (COTS)-centric cyber physical systems often contain software and hardware elements with life-spans shorter than the systems' intended life-span. Various studies have examined hardware obsolescence, although in most systems, software costs contribute as much, or more, to the total life cycle costs than hardware. The aim of our research effort is to explore, synthesize, and compile past research efforts on obsolescence in the context of COTS-based systems, and propose new ways to overcome related issues. This research effort suggests the need for systematic perspectives to streamline potentially overbearing acquisition processes while focusing on core critical aspects affecting systems sustainment and cost. Significant life cycle costs associated with obsolescence mitigation approaches, therefore, programmatic strategic planning should be adapted to include the context of obsolescence with the objective to improve the efficiency of new COTS-intensive CPS systems with enduring perspectives. The study reveals opportunities and challenges for obsolescence in COTS-based CPSs.
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| 5. |
- Cuenot, P., et al.
(author)
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Engineering support for automotive embedded systems beyond autosar
- 2009
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In: AutoTechnology. - 1616-8216. ; 9:2, s. 46-50
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Journal article (peer-reviewed)abstract
- The future de-facto standard for automotive Electric/Electronic (E/E) software architectures of the AUTomotive Open System ARchitecture (Autosar) initiative is gaining momentum in the automotive industry. This is manifested by the fact that vehicle manufacturers and Tier-1 suppliers are committed to this standard. The initiative's main focus is on software (SW) components at implementation level. EAST-ADL2 is an architecture description language, which is based on Autosar concepts and extends the initiative towards a system engineering approach for automotive embedded software.
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| 6. |
- Hashemi, J, et al.
(author)
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Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families.
- 2001
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In: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 31:2, s. 107-16
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Journal article (peer-reviewed)abstract
- Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52-167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow approximately 1-cM region on 9p21.
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| 7. |
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| 8. |
- Parsons, Michael T, et al.
(author)
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Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants : An ENIGMA resource to support clinical variant classification
- 2019
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; , s. 1557-1578
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Journal article (peer-reviewed)abstract
- The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.
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| 9. |
- Pelttari, L. M., et al.
(author)
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Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication
- 2018
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In: Clinical Genetics. - : Wiley. - 0009-9163. ; 93:3, s. 595-602
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Journal article (peer-reviewed)abstract
- Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n=1149), in unselected breast (n=1729) and ovarian cancer cohorts (n=553), and in population controls (n=1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P=.032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
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| 10. |
- Poynter, Jenny N., et al.
(author)
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Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study
- 2010
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In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 21:6, s. 839-846
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Journal article (peer-reviewed)abstract
- Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers. The WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers. None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers. For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.
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| 11. |
- Rozenblum, E, et al.
(author)
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A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes
- 2002
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In: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 110:2, s. 111-121
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Journal article (peer-reviewed)abstract
- Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer.
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| 12. |
- Thomassen, Mads, et al.
(author)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Journal article (peer-reviewed)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 13. |
- Winter, C, et al.
(author)
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Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic
- 2016
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In: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 27:8, s. 8-1532
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Journal article (peer-reviewed)abstract
- BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear.PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden.RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years).CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.
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| 14. |
- Yang, Y., et al.
(author)
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Towards a taxonomy of technical debt for COTS-intensive cyber physical systems
- 2019
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In: 17th Annual Conference on Systems Engineering Research (CSER). - : Elsevier. ; , s. 108-117
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Conference paper (peer-reviewed)abstract
- Most existing studies addressing COTS obsolescence issues in Cyber-Physical Systems (CPSs) have strong emphasis on the sustainment phases. We have identified a gap on methods, processes, and tools for effective COTS risk analysis in the early systems acquisition phases. To fill the gap, this study proposes a taxonomy of COTS-related technical debt in order to support early identification, communication, and assessment of obsolescence risks in CPS system engineering life cycles. The taxonomy contributes to the identification of seven key types of COTS technical debt according to systematic signs discoverable during early COTS activities, which may contribute to obsolescence in later phases. These seven types of COTS technical debt include COTS functionality mismatch, performance mismatch, interoperability difficulty, versioning frequency, documentation and support readiness, and limitation on system evolution. It is expected that such notions will help to increase the efficiency of COTS-based CPS development, readiness, and sustainment, through more informed COTS decision-making to avoid expensive and unaffordable obsolescence issues in the envisioned systems sustainment phases.
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