The role of the BRCA2 gene in susceptibility to prostate cancer revisited.

Prostate cancer is a genetically complex disease with multiple predisposing factors affecting presentation, progression, and outcome. Epidemiologic studies have long shown an aggregation of breast and prostate cancer in some families. More recently, studies have reported an apparent excess of prostate cancer cases among BRCA2 mutation-carrying families.

Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer.

Background: The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer.

Methods: In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies.

Survey sequencing and radiation hybrid mapping to construct comparative maps.

Radiation hybrid (RH) mapping has become one of the most well-established techniques for economically and efficiently navigating genomes of interest. The success of the technique relies on random chromosome breakage of a target genome, which is then captured by recipient cells missing a preselected marker. Selection for hybrid cells that have DNA fragments bearing the marker of choice, plus a random set of DNA fragments from the initial irradiation, generates a set of cell lines that recapitulates the genome of the target organism several-fold.

Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer.

Checkpoint kinase 2 (CHEK2) is a protein involved in arresting cell cycle in response to DNA damage. To investigate whether it plays an important role in the development of prostate cancer (PRCA) in the Ashkenazi Jewish (AJ) population, we sequenced CHEK2 in 75 AJ individuals with prostate, breast, or no cancer (n=25 each). We identified seven coding SNPs (five are novel) that changed the amino-acid sequence, resulting in R3W, E394F, Y424H, S428F, D438Y, P509S, and P509L.

Association of megalin genetic polymorphisms with prostate cancer risk and prognosis.

Purpose: Megalin, an endocytic receptor expressed by prostate epithelial cells, can internalize biologically active androgens bound to sex hormone binding globulin. Genetic variation within megalin could potentially influence levels of steroid hormone uptake.

Experimental Design: Forty haplotype-tagging single-nucleotide polymorphisms (htSNP) were analyzed in a population-based, case-control study of 553 Caucasian men who were diagnosed with prostate cancer between the ages of 40 and 64 years from the Seattle-Puget Sound region and 534 control men.

Statin use and risk of prostate cancer: results from a population-based epidemiologic study.

Epidemiologic studies of statin use in relation to prostate cancer risk have been inconclusive. Recent evidence, however, suggests that longer-term use may reduce risk of more advanced disease. The authors conducted a population-based study of 1,001 incident prostate cancer cases diagnosed in 2002-2005 and 942 age-matched controls from King County, Washington, to evaluate risk associated with statin use.

Single-nucleotide-polymorphism-based association mapping of dog stereotypes.

Phenotypic stereotypes are traits, often polygenic, that have been stringently selected to conform to specific criteria. In dogs, Canis familiaris, stereotypes result from breed standards set for conformation, performance (behaviors), etc. As a consequence, phenotypic values measured on a few individuals are representative of the breed stereotype.

Prostate cancer susceptibility loci: finding the genes.

Studies to date suggest that PC is a genetically very heterogeneous disease. High-risk families, in which multiple men are affected likely, reflect the contributions of a number of genes, some that are rare and highly penetrant, while others are more common and weakly penetrant. In this review, we have discussed only the first type of loci, and found that the identification of such genomic regions is a formidable problem.

Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk.

Recently, the 8q24 region has been identified as a prostate cancer susceptibility locus in a genome-wide scan of prostate cancer families in Iceland and an admixture scan of African Americans. Further investigations of variants at 8q24 have shown the existence of additional single nucleotide polymorphisms (SNPs) that enhance prostate cancer risk, suggesting the possibility of multiple regions harboring variants for the disease. In the present population-based study of Caucasians (1,308 cases and 1,266 controls) and African Americans (149 cases and 85 controls), we tested the association between prostate cancer and 23 SNPs in the 8q24 region.

Diabetes mellitus and prostate cancer risk.

Background: Epidemiological evidence suggests that diabetes mellitus (DM) is associated with a decrease in risk for prostate cancer (PCa). The objective of this study was to examine the association between PCa risk and several characteristics of DM (duration, age at diagnosis, treatment) in data from two population-based, case-control studies of PCa.

Methods: PCa cases (n = 1,752), and controls (n = 1,644) were residents of King County, Washington identified using the Surveillance, Epidemiology, and End Results Seattle-Puget Sound cancer registry and random digit dialing, respectively.

Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model.

There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds.

Searching for epistasis and linkage heterogeneity by correlations of pedigree-specific linkage scores.

Recognizing that multiple genes are likely responsible for common complex traits, statistical methods are needed to rapidly screen for either interacting genes or locus heterogeneity in genetic linkage data. To achieve this, some investigators have proposed examining the correlation of pedigree linkage scores between pairs of chromosomal regions, because large positive correlations suggest interacting loci and large negative correlations suggest locus heterogeneity (Cox et al. [1999]; Maclean et al.

Evaluation of a variant in the transcription factor 7-like 2 (TCF7L2) gene and prostate cancer risk in a population-based study.

Background: Transcription factor 7-like 2 (TCF7L2) is a high mobility group-box containing protein that is a critical member of the Wnt/beta-catenin canonical signaling pathway. In addition to its recently recognized role in diabetes, aberrant TCF7L2 expression has been implicated in cancer through regulation of cell proliferation and apoptosis by c-MYC and cyclin D. It has been hypothesized that germline variants within the TCF7L2 gene previously associated with diabetes may affect cancer risk through the Wnt/beta-catenin signaling pathway.

Canine behavioral genetics: pointing out the phenotypes and herding up the genes.

An astonishing amount of behavioral variation is captured within the more than 350 breeds of dog recognized worldwide. Inherent in observations of dog behavior is the notion that much of what is observed is breed specific and will persist, even in the absence of training or motivation. Thus, herding, pointing, tracking, hunting, and so forth are likely to be controlled, at least in part, at the genetic level.

Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies.

Background: In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions.

Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women.

Introduction: The involvement of vitamin D receptor (VDR), which is a key mediator in the vitamin D pathway, in breast cancer etiology has long been of interest.

Methods: We examined the association between polymorphisms in the 3' end of the VDR gene, specifically BsmI and Poly(A), and breast cancer risk within a large, population-based, case-control study of breast cancer. Cases (n = 1,631) were Caucasian and African-American women, aged 35 to 64 years, who were diagnosed with incident, invasive breast cancer between July 1994 and April 1998.

Fine mapping of familial prostate cancer families narrows the interval for a susceptibility locus on chromosome 22q12.3 to 1.36 Mb.

Genetic studies suggest that hereditary prostate cancer is a genetically heterogeneous disease with multiple contributing loci. Studies of high-risk prostate cancer families selected for aggressive disease, analysis of large multigenerational families, and a meta-analysis from the International Consortium for Prostate Cancer Genetics (ICPCG), all highlight chromosome 22q12.3 as a susceptibility locus with strong statistical significance.

Lessons learned from the dog genome.

Extensive genetic resources and a high-quality genome sequence position the dog as an important model species for understanding genome evolution, population genetics and genes underlying complex phenotypic traits. Newly developed genomic resources have expanded our understanding of canine evolutionary history and dog origins. Domestication involved genetic contributions from multiple populations of gray wolves probably through backcrossing.

Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer.

Genetic variation in vitamin D-related genes has not been investigated comprehensively and findings are equivocal. We studied the association between polymorphisms across the entire vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) and prostate cancer risk among middle-aged men using a population-based case-control study design. DNA samples and survey data were obtained from incident cases (n = 630), 40 to 64 years old, identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry from 1993 to 1996 and from random controls (n = 565) of similar age without a history of prostate cancer.

Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds.

The features of modern dog breeds that increase the ease of mapping common diseases, such as reduced heterogeneity and extensive linkage disequilibrium, may also increase the difficulty associated with fine mapping and identifying causative mutations. One way to address this problem is by combining data from multiple breeds segregating the same trait after initial linkage has been determined. The multibreed approach increases the number of potentially informative recombination events and reduces the size of the critical haplotype by taking advantage of shortened linkage disequilibrium distances found across breeds.

Validity of models for predicting BRCA1 and BRCA2 mutations.

Background: Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood.

Objective: To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University.

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer.

Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages < or =55 years, highlighting the potential importance of this gene in prostate cancer susceptibility.

A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs.

Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet dog breed that results in a double-muscled phenotype known as the "bully" whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313.

Genome-wide linkage scan of prostate cancer Gleason score and confirmation of chromosome 19q.

Despite evidence that prostate cancer has a genetic etiology, it has been extremely difficult to confirm genetic linkage results across studies, emphasizing the large extent of genetic heterogeneity associated with this disease. Because prostate cancer is common--approximately one in six men will be diagnosed with prostate cancer in their life--genetic linkage studies are likely plagued by phenocopies (i.e.