Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

<p>Abstract</p> <p>Background</p> <p>Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly <it>MLH1 </it>and <it>MSH2</it>, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.</p> <p>Methods</p> <p>We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.</p> <p>Results</p> <p>The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among <it>MLH1 </it>mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in <it>MSH2 </it>carriers (about 54%). The relative risk associated with <it>MLH1 </it>was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for <it>MSH2 </it>decreased with age (from 13.1 at age 30 to 5.4 at age 70).</p> <p>Conclusion</p> <p>This study provides a unique population-based study of CRC risks among <it>MSH2</it>/<it>MLH1 </it>mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.</p

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

A systematic review of interventions to increase awareness of mental health and well-being in athletes, coaches and officials

Full search for the psychinfo database. (DOCX 16 kb

Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1

APE1 is the major nuclease for excising abasic (AP) sites and particular 3′-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC1280), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays – a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen – and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals

Neuroblastoma Cell Lines Contain Pluripotent Tumor Initiating Cells That Are Susceptible to a Targeted Oncolytic Virus

Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents

Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity

Peer reviewe