Publications (11)48.05 Total impact
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Article: Genome-wide linkage of 77 families from the African American Hereditary Prostate Cancer study (AAHPC).
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ABSTRACT: The African American Hereditary Prostate Cancer (AAHPC) Study was designed to recruit families with early-onset disease fulfilling criteria of >or=4 affected. We present a approximately 10 cM genome-wide linkage (GWL) analysis on 77 families including 254 affected and 274 unaffected genotyped. Linkage analysis revealed three chromosomal regions with GENEHUNTER multipoint HLOD scores >or=1.3 for all 77 families at 11q22, 17p11, and Xq21. One family yielded genome-wide significant evidence of linkage (LOD = 3.5) to the 17p11 region with seven other families >or=2.3 in this region. Twenty-nine families with no-male-to-male (MM) transmission gave a peak HLOD of 1.62 (alpha = 0.33) at the Xq21 locus. Two novel peaks >or=0.91 for the 16 families with '>6 affected' occurred at 2p21 and 22q12. These chromosomal regions in the genome warrant further follow-up based on the hypothesis of multiple susceptibility genes with modest effects, or several major genes segregating in small subsets of families.The Prostate 02/2007; 67(1):22-31. · 3.48 Impact Factor -
Article: Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus.
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ABSTRACT: In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.Human Genetics 02/2005; 116(1-2):43-50. · 5.07 Impact Factor -
Article: GeneLink: a database to facilitate genetic studies of complex traits.
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ABSTRACT: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink.BMC Genomics 11/2004; 5:81. · 4.07 Impact Factor -
Article: Combined genome-wide scan for prostate cancer susceptibility genes.
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ABSTRACT: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008). Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.CancerSpectrum Knowledge Environment 09/2004; 96(16):1240-7. · 14.07 Impact Factor -
Article: Genome-wide scanning for linkage in Finnish breast cancer families.
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ABSTRACT: Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses. Here, we report results from a genome-wide linkage analysis of 14 high-risk breast cancer families from Finland. These families tested negative for BRCA1 and BRCA2 germline mutations and showed no linkage to the 13q21 region, recently proposed as an additional susceptibility locus. Suggestive linkage was seen at marker D2S364 (2q32) with a parametric two-point LOD score of 1.61 (theta=0), and an LOD score of 2.49 in nonparametric analyses. Additional genotyping of a 40 cM chromosomal region surrounding the region of interest yielded a maximum parametric two-point LOD score of 1.80 (theta=0) at D2S2262 and a nonparametric LOD score of 3.11 at an adjacent novel marker 11291M1 in BAC RP11-67G7. A nonparametric multipoint LOD score of 3.20 was seen at 11291M1 under the assumption of dominant inheritance. While not providing proof of linkage considering the small number of families and large number of laboratory and statistical analyses performed, these results warrant further studies of the 2q32 chromosomal region as a candidate breast cancer susceptibility locus. Both linkage and association studies are likely to be useful, particularly in other isolated populations.European Journal of HumanGenetics 03/2004; 12(2):98-104. · 4.40 Impact Factor -
Article: Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1.
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ABSTRACT: Previous linkage studies have suggested prostate cancer susceptibility genes located on chromosomes 1, 20, and X. Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2. Presently, these linkage regions and candidate genes appear to explain only a small proportion of hereditary prostate cancer cases suggesting the need for additional whole genome analyses. A genome-wide mode-of-inheritance-free linkage scan, using 405 genetic markers, was conducted on 175 pedigrees, the majority containing three or more affected individuals diagnosed with prostate cancer. Stratified linkage analyses were performed based on previously established criteria. Results based on the entire set of 175 pedigrees showed strong suggestive evidence for linkage on chromosome 17q (LOD = 2.36), with strongest evidence coming from the subset of pedigrees with four or more affected individuals (LOD = 3.27). Race specific analyses revealed strong suggestive evidence for linkage in our African-American pedigrees on chromosome 22q (LOD = 2.35). Genome-wide analysis of a large set of prostate cancer families indicates new areas of the genome that may harbor prostate cancer susceptibility genes. Specifically, our linkage results suggest that there is a prostate cancer susceptibility gene on chromosome 17 that is independent of ELAC2. Further research including combined analyses of independent genome-wide scan data may clarify the most important regions for future investigation.The Prostate 01/2004; 57(4):326-34. · 3.48 Impact Factor -
Article: Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26.
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ABSTRACT: In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families. Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown. The highest LOD scores in the affected-only analyses were found at 11q14, where the two-point LOD score was 2.97 (theta = 0.0 at D11S901), GENEHUNTER heterogeneity LOD (HLOD) of 3.36, and a non-parametric-linkage (NPL) score of 2.67 (P = 0.008). A second positive site was at 3p25-26, with a two-point LOD score of 2.57 (theta = 0.01 at D3S1297), HLOD of 2.15, and NPL score of 2.27 (P = 0.02). The results suggest two HPC regions in the Finnish population, which have not been reported previously and warrant further study.The Prostate 01/2004; 57(4):280-9. · 3.48 Impact Factor -
Article: GeneLink: a database to facilitate genetic studies of complex traits
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ABSTRACT: Abstract Background In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. Results GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. Conclusions GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink .BMC Genomics. 01/2004; -
Article: Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families.
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ABSTRACT: Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease. All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM. Genotype data was analyzed using primarily a non-parametric, multipoint approach, although parametric analyses were performed as well. The strongest evidence for linkage was observed at D4S1615, at 4q21 (LOD of 2.8, P = 0.0002). Two other regions had LOD scores over 2.0: at 9q34 (marker D9S1826, LOD = 2.17, P = 0.0008) and at 2q23 (marker D2S151, LOD = 2.03, P = 0.001). An additional 12 regions had LOD scores over 1.0, including markers at 1q24-25 and 7q22 having scores >1.6. Stratifying the linkage results by age of diagnosis indicated that the linkages to chromosomes 2 and 4 were strongest in families with early and late ages of diagnosis, respectively. Our data implicate several new loci as harboring prostate cancer susceptibility genes, and provide confirmatory evidence of linkage at several loci identified previously in other genome-wide scans, including the three regions (4q21, 9q34, and 2q23) with strongest evidence for prostate cancer linkage. These data also emphasize the need to combine linkage data from large numbers of prostate cancer families in efforts to effectively address the extensive heterogeneity that characterizes genetic aspects of this disease.The Prostate 12/2003; 57(4):320-5. · 3.48 Impact Factor -
Article: Genome‐wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25‐26
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ABSTRACT: BACKGROUND In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families.METHODS Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown.RESULTSThe highest LOD scores in the affected-only analyses were found at 11q14, where the two-point LOD score was 2.97 (θ = 0.0 at D11S901), GENEHUNTER heterogeneity LOD (HLOD) of 3.36, and a non-parametric-linkage (NPL) score of 2.67 (P = 0.008). A second positive site was at 3p25-26, with a two-point LOD score of 2.57 (θ = 0.01 at D3S1297), HLOD of 2.15, and NPL score of 2.27 (P = 0.02).CONCLUSIONS The results suggest two HPC regions in the Finnish population, which have not been reported previously and warrant further study. Prostate 57: 280–289, 2003. © 2003 Wiley-Liss, Inc.The Prostate 10/2003; 57(4):280 - 289. · 3.48 Impact Factor -
Article: Physical and transcript map of the hereditary prostate cancer region at xq27.
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ABSTRACT: We have recently mapped a locus for hereditary prostate cancer (termed HPCX) to the long arm of the X chromosome (Xq25-q27) through a genome-wide linkage study. Here we report the construction of an approximately 9-Mb sequence-ready bacterial clone contig map of Xq26.3-q27.3. The contig was constructed by screening BAC/PAC libraries with markers spaced at approximately 85-kb intervals. We identified overlapping clones by end-sequencing framework clones to generate 407 new sequence-tagged sites, followed by PCR verification of overlaps. Contig assembly was based on clone restriction fingerprinting and the landmark information. We identified a minimal overlap contig for genomic sequencing, which has yielded 7.7 Mb of finished sequence and 1.5 Mb of draft sequence. The transcriptional mapping effort localized 57 known and predicted genes by database searching, STS content mapping, and sequencing, followed by sequence annotation. These transcriptional units represent candidate genes for HPCX and multiple other hereditary diseases at Xq26.3-q27.3.Genomics 02/2002; 79(1):41-50. · 3.02 Impact Factor
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- The Prostate (3)
- The Prostate (2)
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- European Journal of HumanGenetics (1)
Institutions
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2004
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University of Helsinki
Helsinki, Province of Southern Finland, Finland -
University of Tampere
- Laboratory of Cancer Genetics
Tampere, Western Finland, Finland
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2003
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VTT Technical Research Centre of Finland
Espoo, Province of Southern Finland, Finland -
National Human Genome Research Institute
Bethesda, MD, USA
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