Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA 1 . The broad genomic complexity caused by CIN is a hallmark of cancer 2 ; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.CIN has complex consequences, including loss or amplification of driver genes, focal rearrangements, extrachromosomal DNA, micronuclei formation and activation of innate immune signalling 1 . This leads to associations with disease stage, metastasis, poor prognosis and therapeutic resistance 3 . The causes of CIN are also diverse and include mitotic errors, replication stress, homologous recombination deficiency (HRD), telomere crisis and breakage fusion bridge cycles, among others 1,4 .Because of the diversity of these causes and consequences, CIN is generally used as an umbrella term. Measures of CIN either divide tumours into broad categories of high or low CIN 5 , are restricted to a single aetiology such as HRD 6 , are limited to a particular genomic feature such as whole-chromosome-arm changes 7 , or can only be quantified in specific cancer types 8,9 . As a result, there is no systematic framework to comprehensively characterize the diversity, extent and origins of CIN pan-cancer, or to define how different types of CIN within a tumour relate to clinical phenotypes. Here we present a robust analysis framework to quantitatively measure different types of CIN across cancer types.

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Background: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. Material and methods: We deeply sequenced 46 genes in normal skin biopsies from 123 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. Results: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest a loss of fidelity in transcription-coupled repair later in life. Conclusion: Our findings reveal that ageing is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.

The study aimed at assessing the acute physiological effects of running a 65-km vs a 107km mountain ultramarathon. Nineteen athletes (15 males and 4 females) from the shorter race and forty three athletes (26 males and 17 females) from the longer race were enrolled. Body weight, respiratory and lower limb strength were assessed before and after the race. Blood samples were obtained before, after and 24-h post-race. Body weight loss did not differ between races. A decrease in squat jump height (p<0.01; d = 1.4), forced vital capacity (p<0.01; d = 0.5), forced expiratory volume in 1 s (p<0.01; d = 0.6), peak inspiratory flow (p<0.01; d = 0.6) and maximal inspiratory pressure (p<0.01; d = 0.8) was observed after the longer race; while, after the shorter race only maximal inspiratory pressure declined (p<0.01; d = 0.5). Greater post-race concentrations of creatine kinase (p<0.01; d = 0.9) and C-reactive protein (p<0.01; d = 2.3) were observed following the longer race, while high-sensitivity cardiac troponin was higher after the shorter race (p<0.01; d = 0.3). Sodium decreased post-competition only after the shorter race (p = 0.02; d = 0.6), while creatinine increased only following the longer race (p<0.01; d = 1.5). In both groups, glomerular filtration rate declined at post-race (longer race: p<0.01, d = 2.1; shorter race: p = 0.01, d = 1.4) and returned to baseline values at 24 h post-race. In summary, expiratory and lower-limb fatigue, and muscle damage and inflammatory response were greater following the longer race; while a higher release of cardiac troponins was observed after the shorter race. The alteration and restoration of renal function was similar after either race.

BackgroundHuman pigmentation is a polygenic quantitative trait with high heritability. In addition to genetic factors, it has been shown that pigmentation can be modulated by oestrogens and androgens via up- or down-regulation of melanin synthesis. Our aim was to identify possible sex differences in pigmentation phenotype as well as in melanoma association in a melanoma case-control population of Spanish origin.MethodsFive hundred and ninety-nine females (316 melanoma cases and 283 controls) and 458 males (234 melanoma cases and 224 controls) were analysed. We genotyped 363 polymorphisms (single nucleotide polymorphisms (SNPs)) from 65 pigmentation gene regions.ResultsWhen samples were stratified by sex, we observed more SNPs associated with dark pigmentation and good sun tolerance in females than in males (107 versus 75; P = 2.32 × 10−6), who were instead associated with light pigmentation and poor sun tolerance. Furthermore, six SNPs in TYR, SILV/CDK2, GPR143, and F2RL1 showed strong differences in melanoma risk by sex (P < 0.01).ConclusionsWe demonstrate that these genetic variants are important for pigmentation as well as for melanoma risk, and also provide suggestive evidence for potential differences in genetic effects by sex.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0070-1) contains supplementary material, which is available to authorized users.