Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour

The Dragon Stirs: China's Trade Policy for Asia - and the World [Article]

This material published in Arizona Journal of International and Comparative Law is made available by the James E. Rogers College of Law, the Daniel F. Cracchiolo Law Library, and the University of Arizona Libraries. If you have questions, please contact the AJICL Editorial Board at http://arizonajournal.org/contact-us/

Free Trade, Sovereignty, Democracy: The Future of the World Trade Organization

The World Trade Organization ( WTO ), only six years old, faces two formidable challenges. First, it must mobilize support to confront determined and growing attacks from outside groups and individuals who proclaim that the organization lacks democratic accountability and is merely a front for multinational corporations and dehumanizing capitalist values. Second, even as it attempts to mobilize its resources to meet these onslaughts, the WTO finds its own institutional viability jeopardized by internal constitutional flaws that play into the hands of opponents: namely, the pressure to legislate new rules-through a highly efficient new dispute settlement system-that flout the mandate that dispute settlement judgments must neither add to nor diminish the existing rights and obligations of WTO members. The United States faces a different, though related, set of challenges. In a world of increasing technological and economic integration, it must continue to balance and rebalance a defense of national sovereignty against grants of authority over economic and social policy to international organizations such as the WTO. The United States must also devise domestic political mechanisms that provide greater democratic accountability with regard to decisions affecting US international obligations. [CONT