The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The changing face of innovation policy: implications for the Northern Ireland economy

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Growing Pennsylvania's High-Tech Economy: Choosing Effective Investments

Compares Pennsylvania's high-tech economic development incentives, programs, and taxes with those of six competitor states. Includes case studies, program summaries, and analyses using a proprietary model and database. Makes policy recommendations

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Rough Road to Market: Institutional Barriers to Innovations in Africa

Translating R&D and inventive efforts into a market product is characterized by significant financial skills, and the ability to overcome technical and instititonal barriers. Research into and translation of new technologies such as biotechnology products to the market requires even greater resources. This paper aims to understand the key factors that foster or hinder the complex process of translating R&D efforts into innovative products. Different pathways exist in developed countries such as firm-level efforts, the use of IPs, the spin-off of new firms that develop new products, or a mixture of these. Developing countries differ substantially in the kinds of instruments they use because of their considerably weaker institutional environment and for this reason our framework takes a systemic and institutional perspective. The paper comtributes to this issue by examining systemic institutional barriers to commercializing biotechnology in a develping context within a systems of innovation framework.research and development, biotechnology, commercialization, innovation, Africa, learning, institution building

Regional science policy and the growth of knowledge megacentres in bioscience clusters

Changes in epistemology in biosciences are generating important spatial effects. The most notable of these is the emergence of a few Bioscience Megacentres of basic and applied bioscience (molecular, post-genomic, proteomics, etc.) medical and clinical research, biotechnology research, training in these and related fields, academic entrepreneurship and commercial exploitation by clusters of drug discovery start-up and spin-off companies, along with specialist venture capital and other innovation system support services. Large pharmaceutical firms that used to lead such knowledge generation and exploitation processes are becoming increasingly dependent upon innovative drug solutions produced in such clusters, and Megacentres are now the predominant source of such commercial knowledge. Big pharma is seldom at the heart of Megacentres such as those the paper will argue are found in about four locations each in the USA and Europe, but remains important for some risk capital (milestone payments), marketing and distribution of drugs discovered. The reasons for this shift (which is also spatial to some extent) are as follows: first, bioscientific research requires the formation of collaboratory relationships among hitherto cognitively dissonant disciplines molecular biology, combinatorial chemistry, high throughput screening, genomics, proteomics and bioinformatics to name a few. Second, the canonical chance discovery model of bioscientific research is being replaced by rational drug design based on those technologies because of the need massively to reduce search costs and delivery timeframes. Third, the US and to some extent European 'Crusade against Cancer' and other pathologies has seen major increases in basic research budgets (e.g. to $27.3 billion in 2003 for the US National Institutes of Health) and foundation expenditure (e.g.$1billion in 2003 by the UK's Wellcome Trust; $1 billion approximately by the top ten US medical foundations, and a comparable sum from corporate foundations). Each of these tendencies weakens the knowledge generation role of 'big pharma'and strengthens that of Megacentres. But the process also creates major, new regional disparities, which some regional governances have recognised, causing them to develop responsibilities for regional science policy and funding to offset spatial biases intrinsic in traditional national (and in the EU, supranational) research funding regimes. Responses follow a variety of models ranging from market following to both regionalised (decentralising by the centre) and regionalist (ground-up), but in each case the role of Megacentres is justified in health terms. But their role in assisting fulfilment of regional economic growth visions is also clearly perceived and pronounced in policy terms.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry