Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees

Farnham, James M.; Camp, Nicola J.; Swensen, Jeff; Tavtigian, Sean V.; Cannon‐Albright, Lisa A.

doi:10.1007/s00439-004-1220-9

Cited by 26 publications

(26 citation statements)

References 26 publications

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“…Six of the 10 ICPCG groups had at least 10 pedigrees in the ''five or more affected men'' subset analysis and four indicated LOD of >1.0 in the same chromosome 22q region [113 pedigrees from Johns Hopkins University (LOD, 1.22), 10 pedigrees from Mayo Clinic (LOD, 2.05), 16 pedigrees from the University of Michigan (LOD, 1.57), and 49 pedigrees from the University of Utah (LOD, 1.31)]. The Utah high-risk prostate pedigree resource has been particularly notable for its ability to significantly confirm previously reported prostate cancer loci (Neuhausen et al (12) for HPC1; Farnham et al (13) for HPCX) and for the localization and identification of HPC2/ELAC2 (14). This is perhaps because the Utah pedigrees are ascertained for significant excess disease and multiple cases, both of which reduce the chance of only sampling clusters of sporadic disease.…”

Section: Introductionmentioning

confidence: 84%

Localization of a Prostate Cancer Predisposition Gene to an 880-kb Region on Chromosome 22q12.3 in Utah High-Risk Pedigrees

Camp¹,

Farnham²,

Cannon‐Albright³

2006

Cancer Research

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Chromosome 22q has become recently a region of interest for prostate cancer. We identified previously a logarithm of odds (LOD) of 2.42 at chromosome 22q12.3. Additionally, this region has been noted by eight other studies, with linkage evidence ranging from LOD of 1.50 to 3.57. Here, we do fine mapping and localization of the region using a pedigreespecific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either ''linked'' or ''haplotype-sharing'' pedigrees or both. ''Linked'' pedigrees were those with significant pedigree-specific linkage evidence (LOD, >0.588; P < 0.05) to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. ''Haplotype-sharing'' pedigrees were those with at least five prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. In each pedigree, the most likely haplotype configuration (in addition to the multipoint LOD graph for linked pedigrees) was used to infer the position of recombinant events and delimit the segregating chromosomal segment in each pedigree. These pedigree-specific chromosomal segments were then overlaid to form a consensus recombinant map across all 14 pedigrees. Using this method, we identified a 881,538-bp interval at 22q12.3, between D22S1265 and D22S277, which is the most likely region that contains the 22q prostate cancer predisposition gene. The unique Utah extended high-risk pedigree resource allows this powerful localization approach in pedigrees with evidence for segregating predisposition to prostate cancer. We are mutation screening candidate genes in this region to identify specific genetic variants segregating in these pedigrees.

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Section: Introductionmentioning

confidence: 84%

Localization of a Prostate Cancer Predisposition Gene to an 880-kb Region on Chromosome 22q12.3 in Utah High-Risk Pedigrees

Camp¹,

Farnham²,

Cannon‐Albright³

2006

Cancer Research

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“…In this study, family members from prostate cancer pedigrees in the United States, Finland, and Sweden were genotyped. Later, the prostate cancer linkage at this region was confirmed by independent replication studies (Lange et al 1999;Xu et al 2003;Brown et al 2004;Gillanders et al 2004;Farnham et al 2005) and by the analysis of 104 German prostate cancer families (Bochum et al 2002).…”

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confidence: 85%

Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27

Kouprina¹,

Pavlı́ček²,

Noskov

et al. 2005

Genome Res.

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Genetic linkage studies indicate that germline variations in a gene or genes on chromosome Xq27-28 are implicated in prostate carcinogenesis. The linkage peak of prostate cancer overlies a region of ∼750 kb containing five SPANX genes (SPANX-A1, -A2, -B, -C, and -D) encoding sperm proteins associated with the nucleus; their expression was also detected in a variety of cancers. SPANX genes are >95% identical and reside within large segmental duplications (SDs) with a high level of similarity, which confounds mutational analysis of this gene family by routine PCR methods. In this work, we applied transformation-associated recombination cloning (TAR) in yeast to characterize individual SPANX genes from prostate cancer patients showing linkage to Xq27-28 and unaffected controls. Analysis of genomic TAR clones revealed a dynamic nature of the replicated region of linkage. Both frequent gene deletion/duplication and homology-based sequence transfer events were identified within the region and were presumably caused by recombinational interactions between SDs harboring the SPANX genes. These interactions contribute to diversity of the SPANX coding regions in humans. We speculate that the predisposition to prostate cancer in X-linked families is an example of a genomic disease caused by a specific architecture of the SPANX gene cluster.

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“…The extended Utah high-risk prostate pedigrees have already provided evidence for the first rare prostate cancer predisposition gene [HPC2/ ELAC2, Tavtigian et al, 2001], and have provided significant confirmations for the HPC1 and HPCX prostate cancer predisposition linkage regions [Neuhausen et al, 1999;Farnham et al, 2005]. There have been multiple other prostate cancer predisposition gene localizations; but it is the exception rather than the rule, that such localizations are validated with independent sets of pedigrees [Easton et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

Identification and study of Utah pseudo‐isolate populations—prospects for gene identification

Cannon‐Albright

Farnham

Thomas

et al. 2005

American J of Med Genetics Pt A

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Isolate populations of varied types have proven powerful for gene identification for rare Mendelian disorders, and continue to show such promise for more complex phenotypes. Existing isolate populations are limited in the phenotypes available for study, and new population isolates are unlikely to arise. We utilize genealogical data available for the state of Utah, dating back to its European founders, to retrospectively define and examine pseudo‐isolate subpopulations. These pseudo‐isolate populations are defined by selection of a set of “founders” from the genealogical data, and then limitation of “immigration” by censoring of matings and offspring that do not match the isolate population design. A wide variety of pseudo isolate and other study designs are possible by varying the number and type of founders and the extent of immigration allowed. We present several different example Birth‐Country pseudo‐isolate populations defined within the Utah Population Database (UPDB). We utilize linked cancer phenotype data available for the Utah population to show the utility of this pseudo‐isolate approach for identification of more genetically homogeneous prostate cancer pedigrees for predisposition gene identification. In conclusion, we present a unique approach to retrospective “creation” of isolate populations using existing genealogical data. We use the UPDB to exhibit the utility of this approach for the highly heterogeneous Utah population, and suggest the approach is feasible for any population for which high quality genealogy and phenotype data are available. © 2005 Wiley‐Liss, Inc.

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Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees

Cited by 26 publications

References 26 publications

Localization of a Prostate Cancer Predisposition Gene to an 880-kb Region on Chromosome 22q12.3 in Utah High-Risk Pedigrees

Localization of a Prostate Cancer Predisposition Gene to an 880-kb Region on Chromosome 22q12.3 in Utah High-Risk Pedigrees

Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27

Identification and study of Utah pseudo‐isolate populations—prospects for gene identification

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