Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer

Negative emotional narratives

Negative emotional narratives are a type of retelling that individuals produce after having experienced a negative emotional episode. They might have either a written or oral form and Always presuppose an addressee, real or symbolic (i.e., a diary), to whom the content is exposed. Following a negative event, individuals narrate what they have experienced along with expressing their emotional feelings and referring personal evaluations and associated meanings. If follows that negative emotional narratives do not simply correspond to objective reproductions of unpleasant facts; instead they are personal reconstructions of memory contents intertwined into the individual’s life story

Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells

Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells

The influence of environmental changes on local and regional vegetation patterns at Rieme (NW Belgium): implications for Final Palaeolithic habitation

Late-glacial vegetation changes were studied at Rieme, NW Belgium. Human occupation of this cover sand area occurred from the Final Palaeolithic onwards. The research area is situated on the northern side of a large cover sand ridge in an undulating landscape with small ridges and depressions. The past landscape was reconstructed using a multi-disciplinary approach, including geomorphological, sedimentological, loss-on-ignition, botanical (micro- and macrofossil) and zoological analyses. AMS 14C dating provided an accurate chronology for the sediments. Analyses were performed on three sequences located ~200–300 m apart. Our study shows that during the Bølling (GI-1e) wet meadows developed on the sandy soils and groundwater levels increased probably as result of permafrost melting. Shallow pools formed in depressions. During the Older Dryas (GI-1d) shrubs with juniper, seabuckthorn and willow developed. Many shallow depressions were overblown with sand and deposition of organic material almost ceased. In the early Allerød (GI-1c) open birch woodlands developed. Due to the final melting of permafrost, groundwater levels rose further and ponds with floating-leaved open water vegetation developed. Large water level fluctuations occurred in one of the ponds. Accumulation of organic deposits ceased during the mid- Allerød. Indirect evidence for human occupation during the Allerød (GI-1c) was found in indications of burning of the reed-swamps in combination with the presence of large herbivores. Final Palaeolithic people probably used the northern side of the cover sand ridge as hunting area, while they settled their temporary (base) camps on the steep southern side along the extensive and deeper Moervaart lake