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International audience; Infectious disease outbreaks, such as 'Coronavirus disease 2019' (COVID-19), can constitute major global health threats with far-reaching consequences. As outbreaks develop, the international scientific community must provide high-quality scientific research-ready biological samples to solve the existing clinical and epidemiological questions to better combat the pandemic. Such examples are provided by dedicated biobank facilities, the latter collecting increasingly high volumes of biological samples. However, the more significant concentrations of infectious or potentially infectious biological materials can create a safety risk. The current short report describes the first attempt to identify the published scientific works on biobanking and safety. Three broad thematic areas have been identified: the physical security relevant to staff and sample integrity, the data safety aspects, and the governance parameters relating to the previous two. While the current publications reflect a broad alignment with existing standards and best practices in the biobanking field, they also demonstrate an opportunity for further in-depth work on this field in the post-COVID-19 era.

BackgroundIn Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study on breast cancer in premenopausal women.MethodsPathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6 and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures.ResultsThe majority of cases were positive for ER or PR (168/233; 72%) and there were 21% triple negative (TN) cases, mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases,TP53andPIK3CAwere the most frequently mutated genes (32.5% and 21.4%, respectively), followed byAKT1(9.5%).TP53mutations were more frequent in HER2-enriched and TN IHC subtypes, whilePIK3CA/AKT1mutations were more frequent in ER positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed inTP53gene in PRECAMA cases compared to TCGA and METABRIC breast cancer series (27% vs 14%). Exome-wide mutational patterns in 10 TN cases revealed alterations in signaling transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways.ConclusionsThis pilot results on PRECAMA tumors gives a preview of the molecular features of premenopausal BC in LA. Although, the overall mutation burden was as expected from data in other populations, mutational patterns observed inTP53and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared to other populations. Further omics analyses of a larger number of cases in the near future will allow investigating relationships between these molecular features and risk factors.

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide‐ and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.A 40-word summaryInnovative experimental approaches identify a novel mutational signature of glycidamide, a metabolite of the probable human carcinogen acrylamide. The results may elucidate the cancer risks associated with exposure to acrylamide, commonly found in tobacco smoke, thermally processed foods and beverages.

Background: Dietary exposure to cytotoxic and carcinogenic aristolochic acid (AA) causes severe nephropathy typically associated with urologic cancers. Monitoring of AA exposure uses biomarkers such as aristolactam-DNA adducts, detected by mass spectrometry in the kidney cortex, or the somatic A>T transversion pattern characteristic of exposure to AA, as revealed by previous DNA-sequencing studies using fresh-frozen tumors. Methods: Here, we report a low-coverage whole-exome sequencing method (LC-WES) optimized for multisample detection of the AA mutational signature, and demonstrate its utility in 17 formalin-fixed paraffin-embedded urothelial tumors obtained from 15 patients with endemic nephropathy, an environmental form of AA nephropathy. Results: LC-WES identified the AA signature, alongside signatures of age and APOBEC enzyme activity, in 15 samples sequenced at the average per-base coverage of approximately 10×. Analysis at 3 to 9× coverage revealed the signature in 91% of the positive samples. The exome-wide distribution of the predominant A>T transversions exhibited a stochastic pattern, whereas 83 cancer driver genes were enriched for recurrent nonsynonymous A>T mutations. In two patients, pairs of tumors from different parts of the urinary tract, including the bladder, harbored overlapping mutation patterns, suggesting tumor dissemination via cell seeding. Conclusions: LC-WES analysis of archived tumor tissues is a reliable method applicable to investigations of both the exposure to AA and its biologic effects in human carcinomas. Impact: By detecting cancers associated with AA exposure in high-risk populations, LC-WES can support future molecular epidemiology studies and provide evidence-base for relevant preventive measures. Cancer Epidemiol Biomarkers Prev; 24(12); 1873–81. ©2015 AACR.

Villar, Stephanie Ortiz-Cuaran, Sandra Abedi-Ardekani, Behnoush Gouas, Doriane Nogueira da Costa, Andre Plymoth, Amelie Khuhaprema, Thiravud Kalalak, Anant Sangrajrang, Suleeporn Friesen, Marlin D Groopman, John D Hainaut, Pierre eng Research Support, Non-U.S. Gov't 2012/06/08 06:00 PLoS One. 2012;7(6):e37707. doi: 10.1371/journal.pone.0037707. Epub 2012 Jun 4.; International audience; 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.

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-A highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy. © 2012 Nature America, Inc. All rights reserved.

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.

Hepatocellular carcinoma (HCC) may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C) was detected in 19 (73%) of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.

International audience; Background: The natural history of chronic HBV infection in sub-Saharan Africa is unknown. Data are required to inform WHO guidelines that are currently based on studies in Europe and Asia.Methods: Between 1974 and 2008, serosurveys were repeated in two Gambian villages, and an open cohort of treatment-naive chronic HBV carriers was recruited. Participants were followed to estimate the rates of hepatitis B e (HBeAg) and surface antigen (HBsAg) clearance and incidence of hepatocellular carcinoma (HCC). In 2012-2013, a comprehensive liver assessment was conducted to estimate the prevalence of severe liver disease.Results: 405 chronic carriers (95% genotype E), recruited at a median age of 10.8 years, were followed for a median length of 28.4 years. Annually, 7.4% (95% CI 6.3% to 8.8%) cleared HBeAg and 1.0% (0.8% to 1.2%) cleared HBsAg. The incidence of HCC was 55.5/100 000 carrier-years (95% CI 24.9 to 123.5). In the 2012-2013 survey (n=301), 5.5% (95% CI 3.4% to 9.0%) had significant liver fibrosis. HBV genotype A (versus E), chronic aflatoxin B1 exposure and an HBsAg-positive mother, a proxy for mother-to-infant transmission, were risk factors for liver fibrosis. A small proportion (16.0%) of chronic carriers were infected via mother-to-infant transmission; however, this population represented a large proportion (63.0%) of the cases requiring antiviral therapy.Conclusions: The incidence of HCC among chronic HBV carriers in West Africa was higher than that in Europe but lower than rates in East Asia. High risk of severe liver disease among the few who are infected by their mothers underlines the importance of interrupting perinatal transmission in sub-Saharan Africa.