Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The Role of Alliums and Their Sulfur and Selenium Constituents in Cancer Prevention

Garlic and its sulfur and selenium-containing components are widely known for their cancer preventive activities primarily in preclinical in vitro and in vivo model systems. Most of our common foods including garlic contain very low levels of selenium compounds relative to those of sulfur. Humans consume a substantial portion of their dietary sulfur and selenium in organic forms. Selenium-enriched foods such as garlic, broccoli and wheat are more effective chemopreventive agents than the corresponding regular dietary items. Naturally occurring and synthetic organoselenium compounds are superior cancer chemopreventive agents compared to their corresponding sulfur analogs. Mechanistic studies demonstrate that sulfur and selenium compounds are capable of cell growth inhibition, cell cycle arrest, induction of apoptosis, alterations of phase I and phase II enzyme activities, and histone deacetylase (HDAC) inhibition. The fact that organosulfur and organoselenium compounds can target multiple pathways suggests that these agents can be used directly as chemopreventive and/or therapeutic agents or in combination with other medicinal compounds. The effect of these agents on the aforementioned parameters varies depending on the dose and form (structure) and whether cells are normal or transformed. Whether the protective effects observed in animals and in cell cultures can be applicable to humans remain to be determined. Thus, studies using genomic, proteomic, and metabolomic techniques in well designed small-scale clinical trials are needed to unequivocally evaluate the potential of allium vegetable constituents on biomarkers of risk for specific cancers prior to entering into long-term expensive phase III clinical chemoprevention trials

Loss of Cadherin-Catenin Adhesion System in Invasive Cancer Cells

As described in the previous chapter, the loss of E-cadherin is the key event in epithelial–mesenchymal transition. While downregulation of E-cadherin could occur via aberrant Akt signaling, direct somatic mutations in E-cadherin are frequent in epithelial tumors such as diffuse-type gastric and lobular breast cancers, where they can be found in up to 50% of primary neoplasms (Berx et al. 1998). E-cadherin mutations were also observed in primary endometrial and ovarian carcinomas, albeit with a lower frequency (Risinger et al. 1994; Muta et al. 1996). The consequences of these mutations for EMT and tumor cell invasion are discussed below