Assessing hypoxia in cancer: a data-driven approach

Low levels of cellular oxygen, also known as hypoxia, is a major characteristic of solid tumours. Cancer hypoxia is associated with poor prognosis, resulting in prometastatic and angiogenic effects as well as inducing resistance to both chemo- and radiotherapeutic treatments. Despite the critical role that low oxygen tensions play in cancer progression, the clinical use of hypoxia-targeting treatments is still extremely low due to the absence of both accurate and cost-effective methods available to measure hypoxia. One promising technique to measure hypoxia are gene expression signatures. As opposed to other methods, usually more expensive or invasive, gene expression signatures can be used to measure hypoxia from cancer biopsies, and even in retrospective cohorts. During the last twenty years, more than fifty hypoxia gene expression signatures have been developed. These expression signatures were derived using a variety of computational methods and different experimental conditions. For example, some signatures have been derived in vitro, others in vivo only and others using both approaches including one or more cancer types. As a result, the scientific community has to decide which of the plethora of signatures to use in their experiments and clinical trials, but which signature and which way of summarising a signature into a “score” is most appropriate for which scenario is currently unknown. This work is the largest and most comprehensive analysis and validation of the 53 published hypoxia gene expression signatures to date. Hypoxia gene expression scores were calculated on publicly available gene expression data from ~1,000 cell line samples (the Gene Expression Omnibus) and ~6,000 clinical samples (The Cancer Genome Atlas) and compared to the same score on normoxic samples. These hypoxia signature scores were compared to the scores derived from more than 7.5 million Random Gene Signatures (RGS) to determine whether they were truly able to measure hypoxia. The overall most effective signature and score combination on cell line samples was the Sorensen 2010 signature using the median score. This achieved an impressive 92.84% accuracy in identifying hypoxic samples in 98 cell lines. In clinical samples, the Buffa 2010 signature using the mean score appears most appropriate as it fulfils the three key criteria of a) being on average higher in tumour samples than in normal tissue samples, b) differing in performance compared to random gene signatures c) serving as a strong prognostic marker (using a number of different thresholds) across 10 important tumour types. However, large prospective clinical studies with multiple measures of hypoxia are urgently needed to affirm our recommendation. This work lays down a new benchmark in how to measure hypoxia and the novel method used may transform how gene expression signatures in multiple fields might be evaluated in years to come

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

Background Height and other anthropometric measures are consistently found to associate with differential cancer risk. However, both genetic and mechanistic insights into these epidemiological associations are notably lacking. Conversely, inherited genetic variants in tumour suppressors and oncogenes increase cancer risk, but little is known about their influence on anthropometric traits. Methods By integrating inherited and somatic cancer genetic data from the Genome-Wide Association Study Catalog, expression Quantitative Trait Loci databases and the Cancer Gene Census, we identify SNPs that associate with different cancer types and differential gene expression in at least one tissue type, and explore the potential pleiotropic associations of these SNPs with anthropometric traits through SNP-wise association in a cohort of 500,000 individuals. Results We identify three regulatory SNPs for three important cancer genes, FANCA, MAP3K1 and TP53 that associate with both anthropometric traits and cancer risk. Of particular interest, we identify a previously unrecognised strong association between the rs78378222[C] SNP in the 3' untranslated region (3'-UTR) of TP53 and both increased risk for developing non-melanomatous skin cancer (OR=1.36 (95% 1.31 to 1.41), adjusted p=7.62E−63), brain malignancy (OR=3.12 (2.22 to 4.37), adjusted p=1.43E−12) and increased standing height (adjusted p=2.18E−24, beta=0.073±0.007), lean body mass (adjusted p=8.34E−37, beta=0.073±0.005) and basal metabolic rate (adjusted p=1.13E−31, beta=0.076±0.006), thus offering a novel genetic link between these anthropometric traits and cancer risk. Conclusion Our results clearly demonstrate that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a genetic basis for linking these human phenotypes

Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK

Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing

New role of fat-free mass in cancer risk linked with genetic predisposition.

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

Large scale epidemiological and computational analysis of Biobank genetics and phenotypic data demonstrates that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a genetic basis for linking these human phenotypes

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence.

BackgroundGenome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.MethodsWe analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.ResultsA SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.ConclusionsThese results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC

Bottom-Up Synthesis of Heteroatom-Doped Chiral Graphene Nanoribbons

Bottom-up synthesis of graphene nanoribbons (GNRs) has significantly advanced during the past decade, providing various GNR structures with tunable properties. The synthesis of chiral GNRs, however, has been underexplored and only limited to (3,1)-GNRs. We report herein the surface-assisted synthesis of the first heteroatom-doped chiral (4,1)-GNRs from the rationally designed precursor 6,16-dibromo-9,10,19,20-tetraoxa-9a,19a-diboratetra­benzo­[<i>a</i>,<i>f</i>,<i>j</i>,<i>o</i>]­perylene. The structure of the chiral GNRs has been verified by scanning tunneling microscopy, noncontact atomic force microscopy, and Raman spectroscopy in combination with theoretical modeling. Due to the presence of oxygen–boron–oxygen (OBO) segments on the edges, lateral self-assembly of the GNRs has been observed, realizing well-aligned GNR arrays with different modes of homochiral and heterochiral inter-ribbon assemblies

Heteroatom-Doped Perihexacene from a Double Helicene Precursor: On-Surface Synthesis and Properties

We report on the surface-assisted synthesis and spectroscopic characterization of the hitherto longest periacene analogue with oxygen–boron–oxygen (OBO) segments along the zigzag edges, that is, a heteroatom-doped perihexacene <b>1</b>. Surface-catalyzed cyclodehydrogenation successfully transformed the double helicene precursor <b>2</b>, i.e., 12a,26a-dibora-12,13,26,27-tetraoxa-benzo­[1,2,3-<i>hi</i>:4,5,6-<i>h</i>′<i>i</i>′]­dihexacene, into the planar perihexacene analogue <b>1</b>, which was visualized by scanning tunneling microscopy and noncontact atomic force microscopy. X-ray photoelectron spectroscopy, Raman spectroscopy, together with theoretical modeling, on both precursor <b>2</b> and product <b>1</b>, provided further insights into the cyclodehydrogenation process. Moreover, the nonplanar precursor <b>2</b> underwent a conformational change upon adsorption on surfaces, and one-dimensional self-assembled superstructures were observed for both <b>2</b> and <b>1</b> due to the presence of OBO units along the zigzag edges