Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.Peer reviewe

Horizontal Institutional Interlinkages

The notion of global governance is widely studied in academia and increasingly relevant to politics and policy making. Yet many of its fundamental elements remain unclear in both theory and practice. This book offers a fresh perspective by analyzing global governance in terms of three major trends, as exemplified by developments in global sustainability governance: the emergence of nonstate actors; new mechanisms of transnational cooperation; and increasingly segmented and overlapping layers of authority. The book, which is the synthesis of a ten-year “Global Governance Project” carried out by thirteen leading European research institutions, first examines new nonstate actors, focusing on international bureaucracies, global corporations, and transnational networks of scientists; then investigates novel mechanisms of global governance, particularly transnational environmental regimes, public-private partnerships, and market-based arrangements; and, finally, looks at fragmentation of authority, both vertically among supranational, international, national, and subnational layers, and horizontally among different parallel rule-making systems. The implications, potential, and realities of global environmental governance are defining questions for our generation. This book distills key insights from the past and outlines the most important research challenges for the future

Institutional Interactions at the Crossroads of Trade and Environment: The Dominance of Liberal Environmentalism?

This article argues that institutional interactions that cut across the domains of trade and environment are embedded in overarching norms that shape their evolution and impact. In making this argument, it analyzes three cases of such interactions within the climate change and biosafety regime complexes: those relating to trade-related climate policies and measures, forest carbon sinks, and trade in genetically modified organisms. The analysis highlights the dominance of liberal environmentalism (a set of global norms promoting economic efficiency and environmental improvements through market-based mechanisms) in shaping institutional interactions within these regime complexes, even as liberal environmentalism is contested by key actors. This, in turn, has implications for effective management of institutional interlinkages within regime complexes in global environmental governance