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The search for susceptibility loci in hereditary prostate cancer (HPC) is challenging because of locus and disease heterogeneity. One approach to reduce disease heterogeneity is to stratify families on the basis of the occurrence of multiple cancer types. This method may increase the power for detecting susceptibility loci, including those with pleiotropic effects. We have completed a genome-wide SNP linkage analysis of 96 HPC families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). When only a prostate cancer (PCa) phenotype was considered to be affected, we observed suggestive evidence for linkage (LOD ≥1.86) at 15q14, 18q21 and 19q13 in all families, and at 1p32 and 15q11-q14 in families with two or more CCa cases. When both the PCa and CCa phenotypes were considered affected, suggestive evidence for linkage was observed at 11q25, 15q14 and 18q21 in all families, and at 1q31, 11q14 and 15q11-14 in families with two or more CCa cases. The strongest linkage signal was identified at 15q14 when both PCa and CCa phenotypes were considered to be affected in families with two or more CCa cases (recessive HLOD=3.88). These results provide further support for the presence of HPC susceptibility loci on chromosomes 11q14, 15q11-q14 and 19q13 and highlight loci at 1q31, 11q, 15q11-14 and 18q21 as having possible pleiotropic effects. This study shows the benefit of using a comprehensive family cancer history to create more genetically homogenous subsets of HPC families for linkage analyses. [ABSTRACT FROM AUTHOR]

Purpose: To quantitatively evaluate the utility of a translocator protein (TSPO)-targeted near-infrared (NIR) probe (NIR-conPK11195) for in vivo molecular imaging of TSPO in breast cancer.Procedures: NIR-conPK11195 uptake and TSPO-specificity were validated in TSPO-expressing human breast adenocarcinoma cells (MDA-MB-231). In vivo NIR-conPK11195 biodistribution and accumulation were quantitatively evaluated in athymic nude mice bearing MDA-MB-231 xenografts.Results: Fluorescence micrographs illustrated intracellular labeling of MDA-MB-231 cells by NIR-conPK11195. Quantitative uptake and competition assays demonstrated dose-dependent (p < 0.001) and TSPO-specific (p < 0.001) NIR-conPK11195 uptake. In vivo, NIR-conPK11195 preferentially labeled MDA-MB-231 tumors with an 11-fold (p < 0.001) and 7-fold (p < 0.001) contrast enhancement over normal tissue and unconjugated NIR dye, respectively.Conclusions: NIR-conPK11195 appears to be a promising TSPO-targeted molecular imaging agent for visualization and quantification of breast cancer cells in vivo. This research represents the first study to demonstrate the feasibility of TSPO imaging as an alternative breast cancer imaging approach. [ABSTRACT FROM AUTHOR]

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. Recently, two publications have narrowed the 22q12.3 locus to a 2.18 Mb interval using 54 high-risk families from the ICPCG collaboration, as defined by three recombination events on either side of the locus. In this paper, we present the results from fine mapping studies at 22q12.3 using both haplotype and recombination data from 42 high-risk families contributed from the Mayo Clinic and the Prostate Cancer Genetic Research Study (PROGRESS) mapping studies. No clear consensus interval is present when all families are used. However, in the subset of 14 families with ≥5 affected men per family, a 2.53-Mb shared consensus segment that overlaps with the previously published interval is identified. Combining these results with data from the earlier ICPCG study reduces the three-recombination interval at 22q12.3 to approximately 1.36 Mb. [ABSTRACT FROM AUTHOR]

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., men with prostate cancer due to environmental or lifestyle factors), weakly penetrant alleles, or a combination of both, making it difficult to replicate linkage findings. One way to account for heterogeneous causes is to use clinical information that is related to the aggressiveness of disease as an endpoint for linkage analyses. Gleason grade is a measure of prostate tumor differentiation, with higher grades associated with more aggressive disease. This semi-quantitative score has been used as a quantitative trait for linkage analysis in several prior studies. Our aim was to determine if prior linkage reports of Gleason grade to specific loci could be replicated, and to ascertain if new regions of linkage could be found. Gleason scores were available for 391 affected sib pairs from 183 hereditary prostate cancer pedigrees as part of the PROGRESS study. Analyzing Gleason score as a quantitative trait, and using microsatellite markers, suggestive evidence for linkage ( P-value ≤ 0.001) was found on chromosomes 19q and 5q, with P-values ≤ 0.01 observed on chromosomes 3q, 7q, and 16q. Our results confirm reports of Gleason score linkage to chromosome 19q and suggest new loci for further investigation. [ABSTRACT FROM AUTHOR]