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Search Results: 1 - 10 of 10917 matches for " Pierre Hainaut "
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Interplay between viral infections and genetic alterations in liver cancer
Pierre Hainaut
Iatreia , 2007,
Abstract: With over 500 000 annual deaths, Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and a leading cause of death in developing countries where about 80% of the cases arise. Risk factors include chronic hepatitis infections (hepatitis B, (HBV) and hepatitis C (HCV) viruses), alcohol, dietary contaminants such as falatoxins The incidence shows important geographic variations, accor In southern Asia, HCC development is mainly related to the endemic Hepatitis B Virus (HBV) infection, cases with hot spot mutation in codon 249 (249ser) of TP53 tumor suppressor gene were also described and associated to a low-intermediate exposure rate to Aflatoxin B1 (AFB1). Presence of Hepatitis C Virus (HCV) infection was also detected in 12 - 17% of HCC cases. Despite the increasing number of studies identifying viral/host interactions in viro-induced HCC or describing potential pathways for hepatocarcinogenesis, precise mechanism has not been identified so far. HBV was demonstrated to enhance hepatocarcinogenesis by different manners; HBV chronic infection is associated to active hepatitis (CAH) and cirrhosis which are hepatic complications considered as early stage for HCC development. These complications mobilise the host immune response, the resulting inflammation initiates and selects the first genetic alteration at the origin of loss of cell control. Moreover, HBV can also promote carcinogenesis through genetic instability generated by its common integration in host DNA. HBV proteins, as HBx, was proven to interact with a variety of targets in the host cell including protein or host transcription factor such as, in particular, the p53 protein or the transcription factor E4F, which is implicated in growth, differenciation and senescence. Specific HBV mutations or distinct HBV genotypes are associated to higher risks factors for HCC or hepatic complications leading to HCC. In summary, active HBV replication potentially disrupts gene integrity, may lead to oncogenic activation through several parallel mechanism, and the role of each of these mechanism may vary with the molecular diversity of viral genotypes.
TP53 and Beta-catenin mutations in liver tumours
Pierre Hainaut
Iatreia , 2007,
Abstract: HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC) . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin) gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73%) and HCV RNA in 4 cases (15.4% cases), 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6%) including 7 mutations at codon 249 (AGG to AGT, arginine to serine), considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection. CTNNB1 mutations were found in 6/26 cases (23%), 4 of whom also had TP53 mutation. There was no significant association between CTTNB1 mutations and viral infection status. These results suggest that mutagenesis by aflatoxin may have an impact greater than recognized sofar in the etiopathogenesis of HCC in Thailand. Furthermore, TP53 and CTNNB1 mutations do not appear as mutually exclusive, and TP53 249ser mutation is associated with overt HBV infection. Thus, HCC in this context may develop according to a sequence of genetic events that includes both TP53 and CTNNB1 mutations.
The Gambia hepatitis intervention study (GHIS)
Pierre Hainaut
Iatreia , 2007,
Abstract: The Gambia Hepatitis Intervention Study (GHIS) is a collaborative undertaking by the International Agency for Research on Cancer, The Government of the Republic of The Gambia and the Medical Research Council of the United Kingdom. This programme was launched in 1986 with the objective of evaluating the efficacy of Hepatitis B (HB) vaccination in childhood in the prevention of HB infection, chronic liver disease and primary liver cancer in a population at high risk. The implementation of this trial involves three overlapping phases: Phase l (1986-1990): V Vaccination accination of appro approximately ximately 60,000 children. HB vaccine, which was approved by the World Health Organisation, was integrated into the Gambian Expanded Programme of Immunisation (EPI) in a phased manner over a four-year period from July 1986 to February 1990. During this period, two groups of children were recruited, one comprising about 60,000 children who received all vaccines in the EPI schedule plus the HB vaccine, the other comprising a similar number of children who received all vaccines except HB. Since February 1990, HB vaccination is offered to all newborns as part of the EPI schedule in The Gambia. Phase ll (1991-1997): Estimate of efficacy of HB vac- vaccine cine against infection and chronic carriage. Longitudinal and cross-sectional surveys were carried out in selected groups of vaccinated (Group 1) and unvaccinated (Group 2). These two subsets have provided evidence of the short-term efficacy of HB vaccine in preventing infection and chronic carriage. By the end of the first decade of life, the vaccine prevents 84% and 94% of HBV infections and chronic carriage, respectively, despite waning antibody levels during the period. Phase lll (since 1998): Long-term follow-up through Cancer Registration. The aim of this phase is to carry out a surveillance of the population of The Gambia, to identify cases of chronic liver disease (cirrhosis) and liver cancer. A linkage is made between the records of cases occurring in subjects within the age-range of the GHIS cohort, and the GHIS database of vaccinated children, to determine whether the individual belongs to the vaccinated or unvaccinated cohort. The components of Phase III are: 1. Detection and ascertainment of cancer cases and cases of chronic liver disease in the population of The Gambia, through support to liver cancer diagnosis in the public and private health sector, and support to Laboratory and Histopathology Services. 2. Registration of cancer cases and of cases of chronic liver disease through the National Cance
Hepatitis infections, aflatoxin and hepatocellular carcinoma
Pierre Hainaut
Iatreia , 2007,
Abstract: The incidence rates of hepatocellular carcinoma (HCC) show large geographic variations, globally reflecting the prevalence of two main aetiologic factors, hepatitis B (HBV) and/or C (HCV) virus infection and exposure to high levels of aflatoxin in the diet (Chen et al. 1997). The highest incidence rates are observed in regions where most of the population is exposed to both factors, such as in parts of eastern Asia and in sub-Saharan Africa (Parkin et al. 2001). These high incidences are consistent with the fact that HBV chronicity and exposure to aflatoxin have a multiplicative effect of risk for HCC. Depending on aetiology and geographic area, mutations in TP53 show striking differences in prevalence and pattern. In Europe and the US, where alcohol is a major risk factor in addition to viral infections, mutations occur in about 25% of HCC and show as much diversity in their type and codon position as in most other epithelial cancers. However, in high incidence areas such as Mozambique, Senegal, The Gambia (Africa) and Qidong county (China), TP53 is mutated in over 50% of the cases and the vast majority of these mutations are a single missense, hotspot mutation at codon 249, AGG to AGT, resulting in the substitution of arginine into serine (249ser). This mutation is uncommon in regions where aflatoxin is not present at significant levels in the diet. In areas of intermediate exposure to aflatoxin, as for example in Thailand, the prevalence of the 249ser mutation is intermediate between high- and low-incidence areas. Thus, there is a dose-dependent relationship between exposure to aflatoxin, incidence of HCC and prevalence of 249ser mutation. Aflatoxins are toxic and carcinogenic metabolites produced by several varieties of molds, mainly Aspergillus flavus and Aspergillus parasiticum. These molds contaminate a wide range of traditional agricultural products in countries with hot, humid climates, including maize, peanuts and cottonseeds. The toxins are present at significant levels in crops at the time of harvest but their concentration further increases under poor conditions of long term food storage, in particular during the rain season. Thus, in these regions, most inhabitants of rural areas are highly exposed to aflatoxins, with seasonal variations reflecting the consumption of stored versus fresh foodstuff. Population-based surveys have demonstrated the presence of serum aflatoxin-albumin adducts in over 95% of the normal population in The Gambia, West Africa. Exposure starts in the perinatal period, through in utero transfer and breast-feeding, and
The IARC TP53 mutation database: a resource for studying the significance of TP53 mutations in human cancers
Aundrey Petitjean,Pierre Hainaut,Magali Olivier
Iatreia , 2007,
Abstract: The tumor suppressor gene TP53 is frequently inactivated by gene mutations in many types of human sporadic cancers, and inherited TP53 mutations predispose to a wide spectrum of early-onset tumors (Li-Fraumeni et Li-Fraumenilike Syndromes). All TP53 gene variations (somatic and germline mutations, as well as polymorphisms) that are reported in the scientific literature or in SNP databases are compiled in the IARC TP53 Database. This database provides structured data and analysis tools to study mutation patterns in human cancers and cell-lines and to investigate the clinical impact of mutations. It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients. The IARC TP53 web site (http://www-p53.iarc.fr/ ) provides a search interface for the core database and includes a comprehensive user guide, a slideshow on TP53 mutations in human cancer, protocols and references for sequencing TP53 gene, and links to relevant publications and bioinformatics databases. The database interface allows download of entire data sets and propose various tools for the selection, analysis and downloads of specific sets of data according to user's query. Recently, new annotations on the functional properties of mutant p53 proteins have been integrated in this database. Indeed, the most frequent TP53 alterations observed in cancers (75%) are missense mutations that result in the production of a mutant protein that differ from the wildtype by one single amino-acid. The characterization of the biological activities of these mutant proteins is thus very important. Over the last ten years, a great amount of systematic data has been generated from experimental assays performed in yeast and human cells to measure the impact of these mutations on various protein properties: (1) transactivation activities (TA) of mutant proteins on reporter genes placed under the control of various p53 responseelements, (2) capacity of mutant proteins to induce cellcycle arrest or apoptosis, (3) ability to exert dominantnegative effect (DNE) over the wild-type protein, (4) activities of mutant proteins that are independent and unrelated to the wild-type protein (gain of function, GOF). Prediction models based on interspecies protein sequence conservation have also been developed to predict the functional impact of all possible single amino-acid substitutions. These data have been used to produce systematic functional classifications of mutant proteins and these classifications have been integrated in the IARC TP
Role of Obesity in the Risk of Breast Cancer: Lessons from Anthropometry
Amina Amadou,Pierre Hainaut,Isabelle Romieu
Journal of Oncology , 2013, DOI: 10.1155/2013/906495
Abstract:
Role of Obesity in the Risk of Breast Cancer: Lessons from Anthropometry
Amina Amadou,Pierre Hainaut,Isabelle Romieu
Journal of Oncology , 2013, DOI: 10.1155/2013/906495
Abstract: An estimated 1.38 million new cases of breast cancer (BC) are diagnosed each year in women worldwide. Of these, the majority are categorized as invasive ductal cell carcinoma. Subgroups of BC are frequently distinguished into five “intrinsic” subtypes, namely, luminal A, luminal B, normal-like, HER2-positive, and basal-like subtypes. Epidemiological evidence has shown that anthropometric factors are implicated in BC development. Overall consistent positive associations have been observed between high body mass index (BMI) and waist-to-hip ratio (WHR) and the risk of BC among postmenopausal women, while conflicting results persist for premenopausal BC, both for BMI and for other anthropometric parameters as well as across ethnic groups. Furthermore, some evidence suggests that body size, body shape, and weight gain during childhood or adolescence may play a role in the risk of BC. In this paper, we describe the evidence linking anthropometric indices at different ages and BC risk, in order to improve our understanding of the role of body fat distribution in the risk of BC, investigate differences in these associations according to menopausal status and ethnic groups, and discuss the potential biological mechanisms linking body size and BC risk. 1. Introduction Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide, accounting for 23% (1.38 million) of the total new cancer cases in 2008 [1, 2]. The majority of invasive breast neoplasms are categorized as “invasive ductal cell carcinoma, not otherwise specified” (ICD-O 8500/3) [3]. This entity has long been recognized to include tumors with heterogeneous molecular characteristics, characterized by distinct patterns of gene expression [4] and of genomic/genetic alterations [5]. Subgroups of BC are frequently distinguished into luminal A (estrogen/progesterone-positive), luminal B, HER2+, and so-called “triple negative” subtypes [6]. Among these subtypes, HER2+ and basal-like subtypes tend to be more common among premenopausal women, as well as in women of African ancestry. Luminal subtypes are more common in postmenopausal women and among Caucasians [7]. The incidence rates of BC show a heterogeneous distribution, while Western countries present the highest incidence rates, the lowest incidences are observed in low resource countries. BC ranks as the fifth cause of death from cancer overall (458,000 deaths), but is still the most frequent cause of cancer death in women in both developing (269,000 deaths) and developed regions (189,500 deaths) [1]. Incidence and mortality rates have
Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma
Simona Ognjanovic,Ghyslaine Martel,Carlos Manivel,Magali Olivier,Erica Langer,Pierre Hainaut
Sarcoma , 2012, DOI: 10.1155/2012/492086
Abstract: The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS) varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN). Available samples were frozen tumor tissues (=48) and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3%) carrying a TP53 mutation at codon 259 (p.D259Y) and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522) and MDM2 SNP309 (rs no. 2279744)), were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively). The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.
TP53 Mutations and HBX Status Analysis in Hepatocellular Carcinomas from Iran: Evidence for Lack of Association between HBV Genotype D and TP53 R249S Mutations
Behnoush Abedi-Ardekani,Doriane Gouas,Stephanie Villar,Masoud Sotoudeh,Pierre Hainaut
Hepatitis Research and Treatment , 2011, DOI: 10.1155/2011/475965
Abstract: High incidence of HCC is mostly due to the combination of two major risk factors, chronic infection with hepatitis B (HBV) and/or C (HCV) viruses and exposure to the mycotoxin aflatoxin B1, which induces a particular mutation at codon 249 in TP53 (R249S). Eight genotypes of HBV are diversely found in high and low incidence areas. Regardless of documented strong associations between TP53 R249S mutation and HBV genotypes B, C, A or E, there is no report of such association for genotype D despite of the presence of aflatoxin in areas with high prevalence of HBV genotype D. In Iran, 3% of the population is chronically infected with HBV, predominantly genotype D. Twenty-one histologically confirmed HCC cases from Iran were analyzed for TP53 R249S and HBV double mutations 1762T/1764A, hallmarks of more pathogenic forms of HBV. We did not detect any of these mutations. In addition, we report the only case identified so far carrying both R249S mutation and chronic HBV genotype D, a patient from The Gambia in West Africa. This paper suggests that association between HBV genotype D and aflatoxin-induced TP53 mutation is uncommon, explaining the relatively lower incidence of HCC in areas where genotype D is highly prevalent. 1. Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer, accounting for about 5% of all human cancers and the second cause of cancer death in the world [1]. In 2008, an estimated of 748,000 new cases of liver cancer occurred and 696,000 people died of this cancer. Although liver cancer is a global health problem and a major cause of mortality and morbidity, low-income, tropical countries are more commonly affected, and 80% of cases occur in these regions, especially in South-East Asia and Sub-Sahara Africa [2]. HCC is the third most common cancer in China with the age-standardized rate (ASR) of 37.4 and 34.1 per 100,000 person-years in males and females, respectively. In Western Africa, the ASR of HCC is 16.6 in males and 16.5 per 100,000 person-years in females, where this cancer accounts for the second most common cancer [1]. Cancer risk is 2–7 times higher in men than in women but this ratio varies across the world. The most important risk factors for liver carcinogenesis include chronic infections with hepatitis B (HBV) and C (HCV) viruses, chronic alcohol consumption, and consumption of aflatoxin B1 (AFB1) contaminated food. With the presence of about 2 billion people with past or present HBV infection across the world and more than 350 million chronic carriers, HBV remains one of the most common human pathogens and
Increase in Female Liver Cancer in The Gambia, West Africa: Evidence from 19 Years of Population-Based Cancer Registration (1988–2006)
Dominique Sighoko,Maria Paula Curado,Denis Bourgeois,Maimuna Mendy,Pierre Hainaut,Ebrima Bah
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018415
Abstract: Hepatocellular Carcinoma (HCC) is a common malignancy worldwide with a high burden in West Africa. Male to female ratios show consistent bias toward males, the biological bases and variations of which are not well understood. We have used data from the Gambian National Cancer Registry to compare trends in incidence of HCC in both genders.
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