A taxonomy of epithelial human cancer and their metastases

<p>Abstract</p> <p>Background</p> <p>Microarray technology has allowed to molecularly characterize many different cancer sites. This technology has the potential to individualize therapy and to discover new drug targets. However, due to technological differences and issues in standardized sample collection no study has evaluated the molecular profile of epithelial human cancer in a large number of samples and tissues. Additionally, it has not yet been extensively investigated whether metastases resemble their tissue of origin or tissue of destination.</p> <p>Methods</p> <p>We studied the expression profiles of a series of 1566 primary and 178 metastases by unsupervised hierarchical clustering. The clustering profile was subsequently investigated and correlated with clinico-pathological data. Statistical enrichment of clinico-pathological annotations of groups of samples was investigated using Fisher exact test. Gene set enrichment analysis (GSEA) and DAVID functional enrichment analysis were used to investigate the molecular pathways. Kaplan-Meier survival analysis and log-rank tests were used to investigate prognostic significance of gene signatures.</p> <p>Results</p> <p>Large clusters corresponding to breast, gastrointestinal, ovarian and kidney primary tissues emerged from the data. Chromophobe renal cell carcinoma clustered together with follicular differentiated thyroid carcinoma, which supports recent morphological descriptions of thyroid follicular carcinoma-like tumors in the kidney and suggests that they represent a subtype of chromophobe carcinoma. We also found an expression signature identifying primary tumors of squamous cell histology in multiple tissues. Next, a subset of ovarian tumors enriched with endometrioid histology clustered together with endometrium tumors, confirming that they share their etiopathogenesis, which strongly differs from serous ovarian tumors. In addition, the clustering of colon and breast tumors correlated with clinico-pathological characteristics. Moreover, a signature was developed based on our unsupervised clustering of breast tumors and this was predictive for disease-specific survival in three independent studies. Next, the metastases from ovarian, breast, lung and vulva cluster with their tissue of origin while metastases from colon showed a bimodal distribution. A significant part clusters with tissue of origin while the remaining tumors cluster with the tissue of destination.</p> <p>Conclusion</p> <p>Our molecular taxonomy of epithelial human cancer indicates surprising correlations over tissues. This may have a significant impact on the classification of many cancer sites and may guide pathologists, both in research and daily practice. Moreover, these results based on unsupervised analysis yielded a signature predictive of clinical outcome in breast cancer. Additionally, we hypothesize that metastases from gastrointestinal origin either remember their tissue of origin or adapt to the tissue of destination. More specifically, colon metastases in the liver show strong evidence for such a bimodal tissue specific profile.</p

The future distribution of wetland birds breeding in Europe validated against observed changes in distribution

Wetland bird species have been declining in population size worldwide as climate warming and land-use change affect their suitable habitats. We used species distribution models (SDMs) to predict changes in range dynamics for 64 non-passerine wetland birds breeding in Europe, including range size, position of centroid, and margins. We fitted the SDMs with data collected for the first European Breeding Bird Atlas and climate and land-use data to predict distributional changes over a century (the 1970s-2070s). The predicted annual changes were then compared to observed annual changes in range size and range centroid over a time period of 30 years using data from the second European Breeding Bird Atlas. Our models successfully predicted ca. 75% of the 64 bird species to contract their breeding range in the future, while the remaining species (mostly southerly breeding species) were predicted to expand their breeding ranges northward. The northern margins of southerly species and southern margins of northerly species, both, predicted to shift northward. Predicted changes in range size and shifts in range centroids were broadly positively associated with the observed changes, although some species deviated markedly from the predictions. The predicted average shift in core distributions was ca. 5 km yr(-1) towards the north (5% northeast, 45% north, and 40% northwest), compared to a slower observed average shift of ca. 3.9 km yr(-1). Predicted changes in range centroids were generally larger than observed changes, which suggests that bird distribution changes may lag behind environmental changes leading to 'climate debt'. We suggest that predictions of SDMs should be viewed as qualitative rather than quantitative outcomes, indicating that care should be taken concerning single species. Still, our results highlight the urgent need for management actions such as wetland creation and restoration to improve wetland birds' resilience to the expected environmental changes in the future

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

Assessing written work by determining competence to achieve the module-specific learning outcomes.

This chapter describes lasers and other sources of coherent light that operate in a wide wavelength range. First, the general principles for the generation of coherent continuous-wave and pulsed radiation are treated including the interaction of radiation with matter, the properties of optical resonators and their modes as well as such processes as Q-switching and mode-locking. The general introduction is followed by sections on numerous types of lasers, the emphasis being on todayʼs most important sources of coherent light, in particular on solid-state lasers and several types of gas lasers. An important part of the chapter is devoted to the generation of coherent radiation by nonlinear processes with optical parametric oscillators, difference- and sum-frequency generation, and high-order harmonics. Radiation in the extended ultraviolet (EUV) and x-ray ranges can be generated by free electron lasers (FEL) and advanced x-ray sources. Ultrahigh light intensities up to 1021 W/cm2 open the door to studies of relativistic laser–matter interaction and laser particle acceleration. The chapter closes with a section on laser stabilization