Virtually all viruses have evolved molecular instruments to circumvent cell mechanisms that may hamper their replication, dissemination, or persistence. Among these is p53, a key gatekeeper for cell ...division and survival that also regulates innate immune responses. This review summarizes the strategies used by different viruses and discusses the mechanisms deployed by SARS-CoV to target p53 activities.
We propose a typology for the strategies used by different viruses to address p53 functions: hit and run (e.g. IAV, ZIKV), hide and seek (e.g. HIV1), kidnap and exploit (e.g. EBV, HSV1), dominate and suppress (e.g. HR HPV). We discuss the mechanisms by which SARS nsp3 protein targets p53 for degradation and we speculate on the significance for Covid-19 pathogenesis and risk of cancer.
p53 may operate as an intracellular antiviral defense mechanism. To circumvent it, SARS viruses adopt a kidnap and exploit strategy also shared by several viruses with transforming potential. This raises the question of whether SARS infections may make cells permissive to oncogenic DNA damage.
Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene cluster at the lung cancer susceptibility locus 15q25.1. In this study, we show that the CHRNalpha3 gene encoding the ...nAChRalpha3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNbeta4 and CHRNalpha5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNalpha3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNalpha3 promoter and gene reactivation. Restoring CHRNalpha3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha3 in CHRNalpha3-expressing lung cancer cells elicited a dramatic Ca(2+) influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha3 gene in human cancer. In defining a mechanism of epigenetic control of nAChR expression in nonneuronal tissues, our findings offer a functional link between susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs to be theranostic targets for cancer detection and chemoprevention.
Background Obesity has been associated with breast cancer risk in the Caucasian population but the association remains unclear in the Hispanics. Previous studies conducted among Hispanics in the U.S. ...have shown inconsistent results. Purpose The association between anthropometry, body shape evolution across lifetime, and the risk of breast cancer was assessed using a multi-center population-based case–control study conducted in Mexico. Methods One thousand incident cases and 1074 matched control women aged 35–69 years were recruited between 2004 and 2007, and analyzed in 2011–2012. Conditional logistic regression models were used. Results Height was related to an increased risk of breast cancer in both premenopausal ( p trend=0.03) and postmenopausal women ( p trend=0.002). In premenopausal women, increase in BMI; waist circumference (WC); hip circumference (HC); and waist–hip ratio (WHR) were inversely associated with breast cancer risk ( p trends<0.001 for BMI and WC, 0.003 for HC, and 0.016 for WHR). In postmenopausal women, decreased risks were observed for increased WC ( p trend=0.004) and HC ( p trend=0.009) among women with time since menopause <10 years. Further analysis of body shape evolution throughout life showed strong and significant increase in risk of breast cancer among women with increasing silhouettes size over time compared to women with no or limited increase. Conclusions These findings suggest that anthropometric factors may have different associations with breast cancer risk in Hispanic women than in Caucasian women. This study also shows the importance of considering the evolution of body shape throughout life.
Human biospecimens are subjected to collection, processing, and storage that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, ...influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research that uses human tissues, it is crucial that information on the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The BRISQ guidelines are proposed as an important and timely resource tool to strengthen communication and publications on biospecimen‐related research and to help reassure patient contributors and the advocacy community that their contributions are valued and respected. Cancer (Cancer Cytopathol) 2011. Published 2011 by the American Cancer Society.
Human biospecimens are subjected to collection, processing, and storage that can significantly alter their molecular composition and consistency. The BRISQ guidelines are proposed as an important and timely tool to strengthen communication and publications on biospecimen‐related research.
Summary The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early cancer has led to mass newborn testing for this mutation in the State of Paraná, southern ...Brazil. Newborn screening for inherited cancer risk is complex and controversial. In this paper, we discuss the justifications for this screening by considering the medical and scientific evidence for this mutation. R337H has been identified in Brazilian families with Li-Fraumeni or related syndromes predisposing to cancers in childhood (ie, brain, renal, and adrenocortical carcinomas), adolescence (ie, soft tissue and bone sarcomas), and young adulthood (ie, breast cancer). R337H has also been detected in children with adrenocortical carcinoma without a documented family history of cancer. The mutation is estimated to occur in about 0·3% of the population in southern Brazil and is associated with increased cancer risk throughout life. Cancer patterns in families positive for R337H suggest strong genetic modifying effects, making it difficult to predict individual risk. Because protocols for cancer-risk management in Li-Fraumeni or related syndromes are debatable, extreme care should prevail in predictive testing of children for R337H. A detailed assessment of the risks, benefits, and costs is needed to ensure that medical, social, and ethical justifications for newborn screening are met.
The Gambia Hepatitis Intervention Study (GHIS) was designed as a randomised control trial of infant hepatitis B vaccination applied to public health policy, with the main goal of preventing primary ...liver cancer later in adult life in The Gambia. To that effect, the National Cancer Registry of The Gambia (NCR), a population-based cancer registry (PBCR), was established in 1986 to actively collect data on all cancer diagnosis nation-wide. We extracted 20-years (1990-2009) of data to assess for the first time, the evolution of the most common cancers, also describe and demonstrate the role of the PBCR in a hepatitis B and liver cancer prevention programme in this population.
We estimated Age-Standardised Incidence Rates (ASR (W)) of the most common cancers registered during the period by gender. The registration period was divided into four 5-year intervals and incidence rates were estimated for each interval. The most common cancers in males were liver, prostate, lung plus bronchus, non-Hodgkin lymphoma (NHL) and stomach, accounting for 60%, 5%, 4%, 5% and 3%, respectively. Similarly, cancers of the cervix uteri, liver, breast and NHL, were the most common in females, accounting for 33%, 24%, 11% and 4% of the female cancers, respectively.
Cancer incidence has remained relatively stable over time, but as shown elsewhere in sub-Saharan Africa the disease is a threat in The Gambia. The infection related cancers which are mostly preventable (HBV in men and HPV/HIV in women) were the most common. At the moment the data is not enough to detect an effect of hepatitis B vaccination on liver cancer incidence in The Gambia. However, we observed that monitoring case occurrence through PBCR is a key public health pre-requisite for rational planning and implementation of targeted interventions for improving the health of the population.
The tumor suppressor protein p53 is ubiquitously expressed as a major isoform of 53 kD, but several forms of lower molecular weight have been observed. Here, we describe a new isoform, ΔN-p53, ...produced by internal initiation of translation at codon 40 and lacking the N-terminal first transactivation domain. This isoform has impaired transcriptional activation capacity, and does not complex with the p53 regulatory protein Mdm2. Furthermore, ΔN-p53 oligomerizes with full-length p53 (FL-p53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of Mdm2 binding, ΔN-p53 does not accumulate in response to DNA-damage, suggesting that this isoform is not involved in the response to genotoxic stress. However, in serum-starved cells expressing wild-type p53, ΔN-p53 becomes the predominant p53 form during the synchronous progression into S phase after serum stimulation. These results suggest that ΔN-p53 may play a role as a transient, negative regulator of p53 during cell cycle progression.
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults ...due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses. Keywords: Li-Fraumeni syndrome, TP53, Genotype, Phenotype, Cancer predisposition
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent ...between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G → T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥ 67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.
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