Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging “cancer methylome”. In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-β (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC

Recurrent somatic mutations reveal new insights into consequences of mutagenic processes in cancer

The sheer size of the human genome makes it improbable that identical somatic mutations at the exact same position are observed in multiple tumours solely by chance. The scarcity of cancer driver mutations also precludes positive selection as the sole explanation. Therefore, recurrent mutations may be highly informative of characteristics of mutational processes. To explore the potential, we use recurrence as a starting point to cluster >2,500 whole genomes of a pan-cancer cohort. We describe each genome with 13 recurrence-based and 29 general mutational features. Using principal component analysis we reduce the dimensionality and create independent features. We apply hierarchical clustering to the first 18 principal components followed by k-means clustering. We show that the resulting 16 clusters capture clinically relevant cancer phenotypes. High levels of recurrent substitutions separate the clusters that we link to UV-light exposure and deregulated activity of POLE from the one representing defective mismatch repair, which shows high levels of recurrent insertions/deletions. Recurrence of both mutation types characterizes cancer genomes with somatic hypermutation of immunoglobulin genes and the cluster of genomes exposed to gastric acid. Low levels of recurrence are observed for the cluster where tobacco-smoke exposure induces mutagenesis and the one linked to increased activity of cytidine deaminases. Notably, the majority of substitutions are recurrent in a single tumour type, while recurrent insertions/deletions point to shared processes between tumour types. Recurrence also reveals susceptible sequence motifs, including TT[C>A]TTT and AAC[T>G]T for the POLE and ‘gastric-acid exposure’ clusters, respectively. Moreover, we refine knowledge of mutagenesis, including increased C/G deletion levels in general for lung tumours and specifically in midsize homopolymer sequence contexts for microsatellite instable tumours. Our findings are an important step towards the development of a generic cancer diagnostic test for clinical practice based on whole-genome sequencing that could replace multiple diagnostics currently in use

Use of traditional complementary and alternative medicine for HIV patients in KwaZulu-Natal, South Africa.

BACKGROUND: Traditional medicine use has been reported is common among individuals with moderate and advanced HIV disease. The aim of this cross-sectional study was to assess the use of Traditional Complementary and Alternative Medicine (TCAM) for HIV patients prior to initiating antiretroviral therapy in three public hospitals in KwaZulu-Natal, South Africa. METHODS: Using systematic sampling, 618 HIV-positive patients were selected from outpatient departments from three hospitals and interviewed with a questionnaire. RESULTS: TCAM was commonly used for HIV in the past six months by study participants (317, 51.3%) and herbal therapies alone (183, 29.6%). The use of micronutrients (42.9%) was excluded from TCAM since mostly vitamins were provided by the health facility. Herbal therapies were the most expensive, costing on average 128 Rand (US$16) per patient per month. Most participants (90%) indicated that their health care provider was not aware that they were taking herbal therapies for HIV (90%). Herbal therapies were mainly used for pain relief (87.1%) and spiritual practices or prayer for stress relief (77.6%). Multivariate logistic regression with use of herbs for HIV as the dependent variable identified being on a disability grant and fewer clinic visits to be associated with use of herbs, and TCAM use for HIV identified being on a disability grant, number of HIV symptoms and family members not contributing to main source of household income to be associated with TCAM use. CONCLUSION: Traditional herbal therapies and TCAM are commonly used by HIV treatment naïve outpatients of public health facilities in South Africa. Health care providers should routinely screen patients on TCAM use when initiating ART and also during follow-up and monitoring keeping in mind that these patients may not fully disclose other therapies