Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

PMCID: PMC3544714This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Soil-transmitted helminth infections, associated factors and nutritional status in an estate community in Sri Lanka

Objectives: To determine the prevalence, intensity, and risk factors associated with soil transmitted helminth (STH) infections and to explore the association between STH infections and nutritional status of an estate community.Methods: A cross-sectional study was conducted in Hanthana Tea Estate (HTE) in Kandy, Sri Lanka, from September 2013 to November 2014. Demographic data were obtained using an interviewer-administrated structured questionnaire. Haemoglobin and serum albumin concentrations were measured in children. Faecal samples were analyzed by direct smears in saline and iodine and Kato-Katz technique using single-stool samples. Anthropometric measurements were obtained to calculate weight-for-age (WAZ), height-for-age (HAZ), and body-mass-index-for-age (BAZ) to evaluate underweight, stunting and wasting, respectively.Results: A total of 233 children (50% female, aged between 1 and 12 years, mean age 6.2±3.4) and 98 parents (93% female, aged between 20 and 52 years, mean age 33±6.2 years) participated in this study. The prevalence of STH infections in children and adults were 27.4% and 14.3% respectively. Ascaris lumbricoides was found in children and adult populations predominantly (26.6% and 14.3% respectively) followed by Trichuris trichiura (0.8% and 1%).Of the infected group, 57.8% of children and 92.8% of adults had a light infection. Moderate infection was found in 40.6% of the children, and 7.2% of the adults. Only one child had a heavy egg count (≥ 50000). The prevalence of STH infections was significantly higher among children than adults (p = 0.014). Not hand washing before a meal (p = 0.002) and after defecation (p &lt; 0.001), greater de-worming period (p &lt; 0.001), use of shared latrine facilities (p = 0.023) and lower levels of mother`s education (p= 0.035) were significantly associated with STH infections. Children with and without STH infection had comparable levels of nutritional indicators. However, 17.6% (n=41) of stunted, 19.3% (n=45) of wasted and 39.5% (n=92) of underweight children were identified in the present study. In addition, 20.2% (n=47) of the children had a low serum albumin level and 15.9% (n=27) had anaemia.Conclusions: Prevalence of STH infections was notably high in both children (27.4%) and their parents (14.3%), indicating a high level of morbidity among the study population. Therefore, a coordinated control and prevention programme considering the diverse socio-demographic characteristics of estate communities is needed to eliminate STH infections in the study population.</p

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.

A defective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome

Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome

We examined adenomas and cancers from hereditary non-polyposis colorectal cancer (HNPCC) syndrome patients for the presence of frameshift mutations in the smooth-muscle myosin gene, MYH11. Our results show that mutations in MYH11 occur more frequently in cancers than adenomas (P=0.008) and are dependent on microsatellite instability (MSI+)

MLH1 deficiency leads to deregulated mitochondrial metabolism

The DNA mismatch repair (MMR) pathway is responsible for the repair of base–base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15–17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. Inhibition of a number of mitochondrial genes, including POLG and PINK1 can induce synthetic lethality in MLH1-deficient cells. Here we demonstrate for the first time that loss of MLH1 is associated with a deregulated mitochondrial metabolism, with reduced basal oxygen consumption rate and reduced spare respiratory capacity. Furthermore, MLH1-deficient cells display a significant reduction in activity of the respiratory chain Complex I. As a functional consequence of this perturbed mitochondrial metabolism, MLH1-deficient cells have a reduced anti-oxidant response and show increased sensitivity to reactive oxidative species (ROS)-inducing drugs. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in MLH1-deficient cells and a requirement for MLH1 in the regulation of mitochondrial function

Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance

AN, HT and AP are Constance Travis post-graduate fellows. NS is a Barts and The London post-doctoral fellow. SMD is a Bowel & Cancer Research post-doctoral fellow. TS is supported by a Grant-in-Aid for scientific research on Innovative Areas, Japan (No. 22134007 to T.S.), and the Yamagata Prefectural Government and City of Tsuruoka

COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.</p

Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre

The introduction of the classification of brain tumours based on their DNA methylation profile has significantly changed the diagnostic approach for cases with ambiguous histology, non-informative or contradictory molecular profiles or for entities where methylation profiling provides useful information for patient risk stratification, for example in medulloblastoma and ependymoma. We present our experience that combines a conventional molecular diagnostic approach with the complementary use of a DNA methylation-based classification tool, for adult brain tumours originating from local as well as national referrals. We report the frequency of IDH mutations in a large cohort of nearly 1550 patients, EGFR amplifications in almost 1900 IDH-wildtype glioblastomas, and histone mutations in 70 adult gliomas. We demonstrate how additional methylation-based classification has changed and improved our diagnostic approach. Of the 325 cases referred for methylome testing, 179 (56%) had a calibrated score of 0.84 and higher and were included in the evaluation. In these 179 samples, the diagnosis was changed in 45 (25%), refined in 86 (48%) and confirmed in 44 cases (25%). In addition, the methylation arrays contain copy number information that usefully complements the methylation profile. For example, EGFR amplification which is 95% concordant with our Real-Time PCR-based copy number assays. We propose here a diagnostic algorithm that integrates histology, conventional molecular tests and methylation arrays

Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the <it>APTX </it>gene were reported in AOA1 patients, mutations in <it>SETX </it>gene were reported in patients with AOA2 and mutations in <it>MRE11 </it>were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia.</p> <p>Methods</p> <p>This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (<it>APTX</it>, <it>SETX </it>and <it>MRE11</it>).</p> <p>Results</p> <p>A novel nonsense truncating mutation c.6859 C > T, R2287X in <it>SETX </it>gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in <it>MRE11 </it>gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia.</p> <p>Conclusion</p> <p>Mutations in <it>APTX </it>, <it>SETX </it>and <it>MRE11 </it>are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in <it>SETX </it>and <it>MRE11 </it>genes but failed to identify mutations in <it>APTX </it>gene.</p

Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue

BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. METHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed. RESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. CONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation