Aflatoxin-Induced TP53 R249S Mutation in HepatoCellular Carcinoma in Thailand: Association with Tumors Developing in the Absence of Liver Cirrhosis

Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd 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

CC9 Livestock-Associated Staphylococcus aureus Emerges in Bloodstream Infections in French Patients Unconnected With Animal Farming

We report 4 bloodstream infections associated with CC9 agr type II Staphylococcus aureus in individuals without animal exposure. We demonstrate, by microarray analysis, the presence of egc cluster, fnbA, cap operon, lukS, set2, set12, splE, splD, sak, epiD, and can, genomic features associated with a high virulence potential in human

Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia.

ABSTARCT: Hepatitis B virus (HBV) occult infection (OBI) is a risk factor to be taken into account in transfusion, hemodialysis and organ transplantation. The aim of this study was to identify and characterize at the molecular level OBI cases in patients with end-stage liver disease. METHODS: Sixty-six liver samples were obtained from patients with diagnosis of end-stage liver disease submitted to liver transplantation in Medellin (North West, Colombia). Samples obtained from patients who were negative for the surface antigen of HBV (n = 50) were tested for viral DNA detection by nested PCR for ORFs S, C, and X and confirmed by Southern-Blot. OBI cases were analyzed by sequencing the viral genome to determine the genotype and mutations; additionally, viral genome integration events were examined by the Alu-PCR technique. RESULTS: In five cases out of 50 patients (10%) the criteria for OBI was confirmed. HBV genotype F (subgenotypes F1 and F3), genotype A and genotype D were characterized in liver samples. Three integration events in chromosomes 5q14.1, 16p13 and 20q12 affecting Receptor-type tyrosine-protein phosphatase T, Ras Protein Specific Guanine Nucleotide Releasing Factor 2, and the zinc finger 263 genes were identified in two OBI cases. Sequence analysis of the viral genome of the 5 OBI cases showed several punctual missense and nonsense mutations affecting ORFs S, P, Core and X. CONCLUSIONS: This is the first characterization of OBI in patients with end-stage liver disease in Colombia. The OBI cases were identified in patients with HCV infection or cryptogenic cirrhosis. The integration events (5q14.1, 16p13 and 20q12) described in this study have not been previously reported. Further studies are required to validate the role of mutations and integration events in OBI pathogenesis

Cancers of the intestine, liver, and biliary tract

Colorectal cancer is an important cancer worldwide, whose etiology is not fully understood. Known causes include several genetic factors, overweight/obesity, tobacco smoking, and heavy alcohol drinking. An etiologic role of diet is highly plausible, but the evidence for specific factors, with the possible exception of processed meat, is not conclusive. Workers exposed to asbestos have been found at increased risk of colorectal cancer in several studies, but the evidence is not sufficiently strong to conclude in favor of a causal association. No other occupational factors have been linked to colorectal cancer. Liver cancer is a common cancer in many regions of the world and is the second cause of cancer-specific mortality. About 75 % of livercancers are hepatocellular carcinoma (HCC), the second most frequent type being cholangiocarcinoma (CCA). HCC develops in the context of a web of interactions between viral (HBV, HCV), environmental (alcohol, aflatoxin), and metabolic (fatty liver disease, obesity) factors. Genetic predisposition accounts for only a small fraction of the global burden of HCC. The only established occupational cause of liver cancer is vinyl chloride, which causes a rare type of neoplasm, angiosarcoma, and has also been associated with HCC. Detection and diagnosis of HCC are complicated by its occurrence in a background of chronic liver disease characterized by inflammation and cycles of hepatocyte proliferation and destruction. Markers used in clinical practice include serological and molecular markers of viral hepatitis, enzymatic tests for liver function and injury, and a growing list of plasma-based tumor markers, the current gold standard being alpha-fetoprotein (AFP). Recent research has identified molecular changes in transcriptome, microRNAome, epigenome, and, significantly, plasma proteome that pave the way to the development of a new generation of biomarkers for early detection of HCC in different etiologic contexts. © Springer-Verlag London 2014

Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects.

International audiencePopulation-based association studies have identified several polymorphic variants in genes encoding ion channel subunits associated with the electrocardiographic heart-rate-corrected QT (QTc) length in healthy populations of Caucasian origin (KCNH2 rs1,805,123 (K897 T) and rs3,815,459, SCN5A rs1,805,126 (D1,819D), 1,141-3 C>A, rs1,805,124 (H558R), and IVS24+116 G>A, KCNQ1 rs757,092, KCNE1 IVS2-128 G>A and rs1,805,127 (G38S), and KCNE2 rs2,234,916 (T8A)). However, few of these results have been replicated in independent populations. We tested the association of SNPs KCNQ1 rs757,092, KCNH2 rs3,815,459, SCN5A IVS24+116 G>A, KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 with QTc length in two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects. All polymorphisms were in Hardy-Weinberg equilibrium in both groups. The minor allele SCN5A IVS24+116 A was more frequent in the group of subjects with the shortest QTc, whereas the minor alleles KCNQ1 rs757,092 G and KCNH2 rs3,815,459 A were more frequent in the group with the longest QTc. There was no significant difference for KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 between the two groups. Haplotype analysis showed a twofold increased risk of QTc lengthening for carriers of the haplotype, combining alleles C and A of the two common KCNE1 SNPs, IVS2-129 C>T (rs2,236,609) and rs1,805,127 (G38S), respectively. In conclusion, our study confirms the reported associations between QTc length and KCNQ1 rs757,092 and KCNH2 rs3,815,459

Relation between Plasma <i>R249S-</i>mutated <i>DNA</i> and HBs-antigen (HBsAg) and HCV-antibody (HCV-ab).

<p><i>X₂</i> test when compared to cholangiocarcinoma, chronic liver disease and reference group all together (*: p value <0.05; ***: p value <0.001; NA: Not Available; ns: non significant).</p

Relation between Plasma <i>R249S-mutated DNA</i> and AFP.

*<p><i>X₂</i> test comparing individuals with <i>R249S</i> > = 150 copies/mL against individuals with <i>R249S</i> <150 copies/mL.</p

Geographic distribution of liver cancer cases.

<p>Dots represent the distribution by province. Pie charts describe the distribution of HCC/no cirrhosis (lines), HCC/cirrhosis (full black) and CC (small dots) among the Northwest, Northeast and Central-south parts of the country.</p

Box and whisker distributions of <i>TP53 R249S</i>-<i>mutated DNA plasma concentrations</i> (≥150 copies/mL) for the different groups.

<p>Boxes extend from 25^th to 75^th percentiles and are divided by a solid line representing the median of each centre. The median levels for the different groups are: 328 in HCC/no cirrhosis, 273 in HCC/cirrhosis, 252 in CC, 256 in CLD and 202 in R.</p