Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

WSES Guidelines for the management of acute left sided colonic diverticulitis in the emergency setting

Acute left sided colonic diverticulitis is one of the most common clinical conditions encountered by surgeons in acute setting. A World Society of Emergency Surgery (WSES) Consensus Conference on acute diverticulitis was held during the 3rd World Congress of the WSES in Jerusalem, Israel, on July 7th, 2015. During this consensus conference the guidelines for the management of acute left sided colonic diverticulitis in the emergency setting were presented and discussed. This document represents the executive summary of the final guidelines approved by the consensus conference.Peer reviewe

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Peer reviewe

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.Peer reviewe

Strategic collaboration councils in the mental health field: What are they working with?

Introduction: In recent years collaboration has become an important part of the delivery of welfare services. One response to these collaborative efforts has been the introduction of strategic collaboration between different welfare agencies. Strategic collaboration is arguably the most open-ended form of service integration, as both purpose and membership are open to negotiation. This article will examine the work in strategic collaboration councils in the mental health services.Method: The study is based on observations in eight strategic collaboration councils in Sweden. The councils were observed over 12 months, and every meeting that was held during that time was observed and tape-recorded.Results: Four basic activities were identified: the exchange of information, the identification of problems, organizing events and activities, and organizing the councils. Even though these activities were identified, the main focus was to exchange information. The councils' work also varied in terms of how they make decisions and agreements, and whether their focus is more on internal or external issues.Conclusion: From the identified activities, the councils can be classified into four ideal types: the information council, the problem-identification council, the decision-making council, and the self-organizing council.

Professionellt gränsarbete - socionomexemplet

The focus of this thesis is on boundary work both as a phenomenon and a theoretical tool, and consists of the manuscripts of four articles and an introduction. One way of perceiving professions is in terms of a landscape metaphor. In this perception of professions, boundaries and boundary work define and separate professional groups by means of dividing social space into sections, over which different groups struggle to establish and maintain control. Different actors make claims on a specific set of boundaries and, in this way, boundary work can be described as either an implicit or an explicit claim-staking activity. The first article, Key metaphors in the sociology of professions: Occupations as hierarchies and landscapes is written in English and offers a comparison between the landscape metaphor and another way of perceiving professions, that of the hierarchy metaphor. If boundaries and boundary work are the most central concepts in the landscape metaphor, closure plays a similar role in the imagery of hierarchies. One conclusion drawn in relation to the two metaphors is that, whilst the landscape provides a finer-tuned theoretical tool, an advantage with the hierarchy metaphor is that it has stronger rhetorical clout. The focus of the second article, which is written in Swedish, is on professional boundary work conducted in a Swedish social welfare department between two groups of qualified social workers, and analyses a specific example of intra-professional boundary work. Among 2 3 the conclusions is that both groups make different claims in the conduct of relational and motivational work carried out from a holistic perspective. The third article, Pragmatic professionalism: Micro level discourse in social work, focuses on boundary work in relation to two ideal types of logic; occupational and organizational professionalism. Perhaps the most important difference between these logics is that, in occupational professionalism, authority is built on trust in the professionals’ education and ethics, whilst in organizational professionalism it is grounded in regulation and control expressed, for example, in rules, regulations and routines. The article deals with how two groups of social workers in Swedish welfare departments position themselves in relation to these logics. Among the conclusions is that the groups relate to the logics in a pragmatic way, making claims on the occupational professionalism but, at times, falling back on organizational professionalism. The fourth and final article, The heroine and the capitalist: The professions´ debate about privatization of Swedish social work, analyzes boundary work conducted in four professional social work journals in the context of debate about privatization. The debate can be described as a struggle with a professional ambivalence towards privatization. This ambivalence is, for instance, evidenced in the metaphorical descriptions of those involved as either heroines or capitalists.Distribution: University of Gothenburg, Department of Social Work, P. O. Box 720, S – 405 30 Götebor

Strategisk samverkan kring personer med psykiska funktionshinder: Om organisering, beslut och beslutsfattande

Samverkan har blivit en allt viktigare styrform i välfärdsproduktionen. Behovet av samverkan förefaller ha ökat på grund av en intensifierad specialisering, arbetsdelning och divisionalisering. Samverkan har setts som lösningen på komplexa och konfliktfyllda problem i produktionen av välfärdstjänster. Syftet med artikeln är att undersöka hur styrning genom strategisk samverkan organiseras och att beskriva och analysera hur rådsmedlemmarna ser på beslut och beslutsfattande i råden.  För att besvara dessa frågor har medlemmar ur åtta strategiska samverkansråd intervjuats och de har dessutom fått besvara en mindre enkät. Resultatet visar att det finns betydande problem i fråga om vem som egentligen bör sitta i dessa råd, samt att man inte alls är överens om hur arbetet i råden ser ut.Collaboration has become an increasingly important way of governance in the welfare state. The need and demand for collaboration have increased due to specialization of professions, divisionalization of organizations and an increasing number of actors, among other things, resulting from the marketization of public services in Sweden. The aim of the article is to describe and analyse how strategic collaboration councils are organized and to consider the council members’ point of view when it comes to decisions and decision-making. The results show that there are some considerable problems and dilemmas in deciding upon who should be in these councils, and that there is no general agreement about what the councils’ work should entail