PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells.

Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for low-level hTERT transcription. Activated and malignant lymphocytes express high telomerase activity, through a mechanism that seems methylation-independent. The aim of this study was to determine which mechanism is involved in the enhanced expression of hTERT in lymphoid cells. Our data confirm that in B cells, some T cell lymphomas and non-neoplastic lymph nodes, the hTERT promoter is unmethylated. Binding sites for the B cell-specific transcription factor PAX5 were identified downstream of the ATG translational start site through EMSA and ChIP experiments. ChIP assays indicated that the transcriptional activation of hTERT by PAX5 does not involve repression of CTCF binding. In a B cell lymphoma cell line, siRNA-induced knockdown of PAX5 expression repressed hTERT transcription. Moreover, ectopic expression of PAX5 in a telomerase-negative normal fibroblast cell line was found to be sufficient to activate hTERT expression. These data show that activation of hTERT in telomerase-positive B cells is due to a methylation-independent mechanism in which PAX5 plays an important role

Use of swabs for dry collection of self-samples to detect human papillomavirus among Malagasy women

Most women in developing countries have never attended cervical screening programmes and often little information exists on type-specific human papillomavirus (HPV) prevalence among these populations. Self-sampling for HPV testing (self-HPV) using a dry swab may be useful for establishing a screening program and evaluating HPV prevalence. Our aim was to evaluate self-HPV using a dry swab stored at room temperature

A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations.

To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease

Focal amplification of genomic loci in selected stage II/III colon cancer samples.

<p>(<b>A–H</b>) Copy number plots for the entire genome arranged in chromosomal order from the short arm of chromosome 1 (1pter) to the long arm of chromosome X (Xqter) for 8 independent tumor samples. Amplicons of particular interest are highlighted with arrows, along with established oncogenes. Details regarding all amplicons and GISTIC peaks are in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042001#pone.0042001.s005" target="_blank">Table S3</a>.</p

Unsupervised hierarchical clustering analysis based of genome-wide copy number data.

<p>(<b>A</b>) Three major clusters. The right-hand annotation indicates, in order, the BRAFm (in yellow, BRAF mutants; in blue, BRAF wild-types), KRASm (mutants in green), and BRAFm-like (in green, BRAFm-like; in red, non-BRAFm-like). Purple color indicates missing values. (<b>B</b>) Genome-wide frequency plot of copy number gain (above axis, blue) and copy number loss (below axis, red) across three major clusters.</p

Summary of copy number aberrations detected in 269 MSS stage II/III colon cancer samples.

<p>(<b>A</b>) Frequencies of copy number gain (above axis, blue) and copy number loss (below axis, red) across the human genome. (<b>B</b>) Significance of focal amplifications detected by GISTIC 2.0. Chromosome positions were indicated along the y axis with centromere positions indicated by dotted lines. The ten most significant GISTIC peaks are shown in red text. Additional GISTIC peaks encoding established oncogenes are in black text. Details for all GISTIC peaks are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042001#pone.0042001.s005" target="_blank">Table S3</a>.</p

Boxplots for WNK1 (A) and HNF4A’s (B) mRNA expression grouped by CNA status.

<p>Tumor samples were categorized by their CNA status (deletion, loss, normal, gain, amplification) for the indicated gene. The panels show the expression level by category for each probeset from the ALMAC platform (see Materials and Methods) representing the specific gene. The values were centered for each probeset; categories are plotted if there was at least one sample in it.</p

Top canonical pathways possibly affected by the amplified genes.

*<p>FDR is based on was calculated based on 100 permutations where random sets of genes of same size were tested.</p

Unsupervised hierarchical clustering indentified three major CNA clusters.

*<p>indicates significant over-representation in the category.</p