Gastric cancer in Iceland

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Genetic correction of PSA values using sequence variants associated with PSA levels

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMeasuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.info:eu-repo/grantAgreement/EC/FP7/202059/ 218071 Urological Research Foundation P50 CA90386-05S2 Robert H. Lurie Comprehensive Cancer Center p30 CA60553 Health Technology Assessment Programme 96/20/06 96/20/99 Department of Health, England Cancer Research UK C522/A8649 Medical Research Council of England G0500966 ID 75466 National Cancer Research Institute (NCRI), UK Southwest National Health Service Research and Development NCRI National Institute for Health Resear

Generation of heterohybridomas secreting human immunoglobulins; pokeweed mitogen prestimulation is highly effective but phytohemagglutinin drives most B cells into apoptosis

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldHuman monoclonal antibodies have commonly been generated by forming hybridomas of stable lymphoblastoid cell lines and Epstein-Barr virus (EBV)-transformed human B cells that have been exposed to phytohaemagglutin (PHA)-stimulated T cells. However, this technique has predominantly given rise to IgM- but very rarely IgG- or IgA-producing clones. We now report that, regardless of prior EBV infection, pokeweed mitogen (PWM) stimulation of human peripheral blood mononuclear cells (PBMCs) generated much higher numbers of IgM-, IgA- and IgG-producing B cells than did stimulation with PHA. Fusion of PWM-stimulated PBMCs with a mouse myeloma cell line also gave rise to 7- to 12-fold higher numbers of IgG- and IgA-producing heterohybridomas than PBMCs that were prestimulated with PHA. Judged by Annexin V staining, stimulation with PHA induced a very high rate of B cell apoptosis within 24 h, whereas, even after 7 days, PWM stimulation only induced marginal B cell apoptosis. This should explain why PHA is much inferior to PWM in stimulating immunoglobulin (Ig) production in vitro and in generating immunoglobulin-producing human B cell hybridomas. It is concluded that PWM stimulation may greatly facilitate the generation of human monoclonal antibodies of all isotypes

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

To access publisher's full text version of this article click on the hyperlink belowBackground: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. Methods: We performed genome-wide association studies of serum levels of AFP (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945), and 125 (N = 9,824), and ALP (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry. Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels. Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood. Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Dental & Craniofacial Research (NIDCR