The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis. These responses have been implicated in an ...individual's ability to suppress tumour formation and to respond to many types of cancer therapy. Here we focus on how best to use knowledge of this pathway to tailor current therapies and develop novel ones. Studies of the genetics of p53 pathway components - in particular p53 itself and its negative regulator MDM2 - in cancer cells has proven useful in the development of targeted therapies. Furthermore, inherited single nucleotide polymorphisms in p53 pathway genes could serve a similar purpose.
Cancer development involves the stepwise accumulation of genetic lesions that overcome the normal regulatory pathways that prevent unconstrained cell division and tissue growth. Identification of the ...genetic changes that cause cancer has long been the subject of intensive study, leading to the identification of several RNA-binding proteins (RBPs) linked to cancer. Cross-reference of the complement of RBPs recently identified by RNA interactome capture with cancer-associated genes and biological processes led to the identification of a set of 411 proteins with potential implications in cancer biology. These involve a broad spectrum of cellular processes including response to stress, metabolism and cell adhesion. Future studies should aim to understand these proteins and their connection to cancer from an RNA-centred perspective, holding the promise of new mechanistic understanding of cancer formation and novel approaches to diagnosis and treatment.
Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers ...remain largely unknown.
We develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data.
We propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.
The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response ...pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to ...somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.
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 rs615029T and rs1485995G 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.
The NRF2/sMAF protein complex regulates the oxidative stress response by occupying cis-acting enhancers containing an antioxidant response element (ARE). Integrating genome-wide maps of NRF2/sMAF ...occupancy with disease-susceptibility loci, we discovered eight polymorphic AREs linked to 14 highly ranked disease-risk SNPs in individuals of European ancestry. Among these SNPs was rs242561, located within a regulatory region of the MAPT gene (encoding microtubule-associated protein Tau). It was consistently occupied by NRF2/sMAF in multiple experiments and its strong-binding allele associated with higher mRNA levels in cell lines and human brain tissue. Induction of MAPT transcription by NRF2 was confirmed using a human neuroblastoma cell line and a Nrf2-deficient mouse model. Most importantly, rs242561 displayed complete linkage disequilibrium with a highly protective allele identified in multiple GWASs of progressive supranuclear palsy, Parkinson’s disease, and corticobasal degeneration. These observations suggest a potential role for NRF2/sMAF in tauopathies and a possible role for NRF2 pathway activators in disease prevention.
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•Genome-wide NRF2/sMAF occupancy defines highly ranked disease-associated SNPs•SNPs in NRF2 binding sites are rare in the human genome due to negative selection•A SNP in MAPT shows allele-specific binding to NRF2, enhanced MAPT transcription•Strong NRF2 binding site is linked with reduced risk of parkinsonian diseases
Wang et al. find that a polymorphic NRF2/sMAF binding site in MAPT is strongly associated with differential risk for parkinsonian disorders and provide evidence that it is occupied by NRF2/sMAF proteins in human and mouse cells. The stronger-binding allele enhances MAPT expression in the human brain and associates with a protective effect in GWAS analyses.
The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a ...polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
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•A common SNP can influence p53’s regulation of a key target gene, the KITLG gene•The SNP in the p53-binding site can significantly influence human cancer risk•The SNP in the p53-binding site has undergone positive natural selection in humans•Similar SNPs in p53-binding sites are rare in the genome due to negative selection
The polymorphism in the KITLG regulatory region associates with differential testicular cancer risk (higher with the G allele, which is more prevalent in Caucasians than in African American males) but also shows signs of positive natural selection, perhaps due to the role of KIT in UV protection in light skinned Caucasians.
The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the ...promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans.
In a recent article, a candidate pathway approach was taken to try to identify single nucleotide polymorphisms (SNP) that make up the genetic variation, which underlies the phenotypic variation seen ...between individuals in their susceptibility to cancer and the progression of their disease. The p53 stress response pathway was chosen given its well-documented importance in tumor suppression. A SNP was found which associates with the attenuation of the p53 pathway and the acceleration of tumor formation in humans and data was presented which describe a molecular mechanism for these phenotypes.
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