Urinary uranium and kidney function parameters in professional assistance workers in the Epidemiological Study Air Disaster in Amsterdam (ESADA)

Background. The Epidemiological Study Air Disaster in Amsterdam (ESADA) aimed to assess long-term health effects in professional assistance workers involved in the 1992 air disaster in Amsterdam. As part of ESADA indications of nephrotoxicity due to exposure to uranium from the balance weights of the crashed aircraft were assessed. Methods. Data of a historically defined cohort of 2499 (exposed and non-exposed) firefighters, police officers and hangar workers were collected 8.5 years after the disaster. Urinary uranium concentrations were determined by sector field inductively coupled plasma mass spectrometry. Urine albumin-creatinine ratio and fractional excretion of β2-microglobulin were calculated from a single-spot urine specimen and simultaneous blood sample. Exposed assistance workers were compared with their non-exposed colleagues, and associations between uranium and kidney function parameters were explored. Results. Median uranium concentrations were around 2 ng/g creatinine. Median values of albumin-creatinine ratio and fractional excretion of β2-microglobulin were well below the level for microalbuminuria and for tubular damage, respectively. No statistically significant differences between exposed and non-exposed workers were found in uranium concentrations and kidney function parameters, although exposed hangar workers had lower uranium concentrations. No statistically significant associations were found between uranium concentrations and kidney function parameters in the total cohort. Conclusions. Occupational exposure to the air disaster in Amsterdam was neither significantly associated with higher uranium concentrations, nor with disturbed kidney function parameters. In this large cohort of professional assistance workers, urinary uranium concentrations were in the low range compared with previously published reference populations. No indications of nephrotoxicity were found at urinary uranium concentrations around 2 ng/g creatinine

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. 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; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes