Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that hereditary prostate cancer (PRCA) is a complex disease, involving multiple susceptibility genes and variable phenotypic expression. Through linkage analysis, potential prostate cancer susceptibility loci have been mapped to 3 regions on chromosome 1. To investigate the reported linkage to these regions, we conducted linkage studies on 144 PRCA families by using microsatellite markers in regions 1q24-25 (HPC1) and 1q42.2-43 (PCAP). We also examined the 1p36 (CAPB) region in 13 PRCA families with at least one case of brain cancer. No significant evidence of linkage to the HPC1 or PCAP region was found when the entire data set was analyzed. However, weak evidence for linkage to HPC1 was observed in the subset of families with male-to-male transmission (n=102; maximum multipoint nonparametric linkage [NPL] 1.99, P=.03). Weak evidence for linkage with heterogeneity within this subset was also observed (HLOD 1.21, P=.02), with approximately 20% of families linked. Although not statistically significant, suggestive evidence for linkage to PCAP was observed for the families (n=21) that met the three criteria of male-to-male transmission, average age of diagnosis <66 years, and >/=5 affected individuals (maximum multipoint NPL 1.45, P=.08). There was no evidence for linkage to CAPB in the brain cancer-prostate cancer subset. These results strengthen the argument that prostate cancer is a heterogeneous disease and that multiple genetic and environmental factors may be important for its etiology.
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PMID:Linkage analyses at the chromosome 1 loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer. 1067 14

A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.
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PMID:Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. 1071 9

Analysis of a genome screen of 504 brothers with prostate cancer (CaP) who were from 230 multiplex sibships identified five regions with nominally positive linkage signals, on chromosomes 2q, 12p, 15q, 16p, and 16q. The strongest signal in these data is found on chromosome 16q, between markers D16S515 and D16S3040, a region suspected to contain a tumor-suppressor gene. On the basis of findings from previous genome screens of families with CaP, three preplanned subanalyses were carried out, in the hope of increasing the subgroup homogeneity. Subgroups were formed by dividing the sibships into a group with a positive family history (FH+) that met criteria for "hereditary" CaP (n=111) versus those which did not meet the criteria (n=119) and by dividing the families into those with a mean onset age below the median (n=115) versus those with a mean onset age above the median (n=115). A separate subanalysis was carried out for families with a history of breast cancer (CaB+ [n=53]). Analyses of these subgroups revealed a number of potentially important differences in regions that were nonsignificant when all the families were analyzed together. In particular, the subgroup without a positive family history (FH-) had a signal in a region that is proximal to the putative site of the HPC1 locus on chromosome 1, whereas the late-age-at-onset group had a signal on 4q. The CaB+ subgroup revealed a strong linkage signal at 1p35.1.
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PMID:A genome screen of multiplex sibships with prostate cancer. 1071 8

Confirmation of linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of cancer susceptibility genes. We report here on an analysis of 150 high-risk prostate cancer families (2,176 individuals) for potential linkage to the HPC1 prostate cancer susceptibility locus at 1q24-25. This dataset includes 640 affected men with an average age at prostate cancer diagnosis of 66. 8 years (range, 39-94), representing the largest collection of high-risk families analyzed for linkage in this region to date. Linkage to multiple 1q24-25 markers was strongly rejected for the sample as a whole (lod scores at theta = 0 ranged from -30.83 to -18. 42). Assuming heterogeneity, the estimated proportion of families linked (alpha) at HPC1 in the entire dataset was 2.6%, using multipoint analysis. Because locus heterogeneity may lead to false rejection of linkage, data were stratified based on homogeneous subsets. When restricted to 21 Caucasian families with five or more affected family members and mean age at diagnosis < = 65 years, the lod scores at theta = 0 remained less than -4.0. These results indicate that the overall portion of hereditary prostate cancer families whose disease is due to inherited variation in HPC1 may be less than originally estimated.
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PMID:Linkage analysis of 150 high-risk prostate cancer families at 1q24-25. 1072 9

Data from many types of studies support the hypothesis that strong familial components are involved in the etiology of prostate cancer. One way to access such genes is through the study of families with multiple affected family members and, in particular, families with individuals affected comparatively early in life. Several prostate cancer susceptibility loci have been described to date. Confirmation of the linkage and estimation of the proportion of families who are linked in large independent datasets is essential to understanding the significance of susceptibility genes. We explore the methodology used to perform such studies and the factors that can limit the ability to confirm linkage results. We report specifically the example of the HPC1 gene on 1q24-25.
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PMID:Confirmation of prostate cancer susceptibility genes using high-risk families. 1085 90

The aim of this study was to investigate allelic imbalance at the major human prostate cancer susceptibility locus HPC1 at 1q24-25 and the recently reported, putative, susceptibility locus at 1p36 in prostate tumors from Swedish families with hereditary prostate cancer. We analyzed 31 prostate tumors and two lymph node metastases from 33 Swedish men in 22 families with hereditary prostate cancer for the presence of allelic imbalance using microsatellite markers D1S158, D1S422, and D1S238 for the HPC1 locus and D1S1597, D1S407, and D1S489 for the 1p36 locus. Frequencies of allelic imbalance at the two investigated loci were quite low, 3 of 27 informative tumors at the 1p36 locus and 3 of 27 informative tumors at the HPC1 locus. Interestingly, two tumors showed allelic imbalance at both loci investigated, suggesting that they may have lost a great part of chromosome 1. Taking this possibility into consideration, the specific loss of the two investigated loci may be even lower (1 of 27 informative tumors for either locus). The very low level of allelic imbalance found at HPC1 and 1p36 makes it unlikely that these loci encode genes that are acting as classic tumor suppressor genes in the initiation or progression of hereditary prostate cancer. Of the eight tumors from HPC1-linked families, only two showed AI at the HPC1 locus, one of which had lost the wild-type allele.
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PMID:Low frequency of allelic imbalance at the prostate cancer susceptibility loci HPC1 and 1p36 in Swedish men with hereditary prostate cancer. 1106 72

Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.
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PMID:Analysis of HPC1, HPCX, and PCaP in Icelandic hereditary prostate cancer. 1112 38

Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPC1 at 1q24-q25 (OMIM #601518) and HPCX at Xq27-q28 (OMIM #300147). Genetically homogeneous populations, such as that of Finland, and distinct subsets of families may help to minimize the genetic heterogeneity that complicates the genetic dissection of complex traits. Here, the role of the HPC1, and HPCX loci in a series of Finnish prostate cancer families was studied, especially in subgroups of families defined by age, number of affected cases, and the mode of disease transmission. DNA samples were collected from 57 Finnish HPC families with at least two living prostate cancer patients. Linkage analysis was carried out with 39 microsatellite markers for the HPC1 region and 22 markers for the HPCX region. The maximum two-point LOD score for the HPCX was 2.05 (marker DXS1205, at theta = 0.14), whereas HPC1 LOD scores were all negative. In HOMOG3R analyses, significant evidence of heterogeneity was observed. Subgroup analyses performed to explore the nature of this heterogeneity indicated that families with no male-to-male (NMM) transmission and a late age of diagnosis (>65 years) accounted for most of the HPCX-linked cases. The maximum HPCX LOD score in this subgroup was 3.12 (theta = 0.001). Nonparametric sibling pair analyses gave a peak LOD score of 3.04 (P < 0.000093) for the NMM transmission subgroup. No subgroup showed any positivity for HPC1. This study suggests that the HPCX-linked prostate cancer families represent a distinct subgroup characterized by NMM transmission of disease and late age of diagnosis.
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PMID:A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. 1115 39

The African American Hereditary Prostate Cancer (AAHPC) Study is an ongoing multicenter genetic linkage study organized by Howard University and the National Human Genome Research Institute (NHGRI), with support from the Office for Research on Minority Health and the National Cancer Institute. The goals of the study are to: (i) look for evidence of involvement of chromosome 1q24-25 (HPC1) in African American men with hereditary prostate cancer (HPC) and (ii) conduct a genome-wide search for other loci associated with HPC in African American men. To accomplish these goals, a network has been established including Howard University, the NHGRI, and six Collaborative Recruitment Centers (CRCs). The CRCs are responsible for the identification and enrollment of 100 African American families. To date, 43 families have been enrolled. Recruitment strategies have included mass media campaigns, physician referrals, community health-fairs/prostate cancer screenings, support groups, tumor registries, as well as visits to churches, barber shops, and universities. By far, the most productive recruitment mechanisms have been physician referrals and tumor registries, yielding a total of 35 (81%) families. Approximately 41% (n = 3400) of probands initially contacted by phone or mail expressed interest in participating; the families of 2% of these met the eligibility criteria, and 75% of those families have been enrolled in the study, indicating a 0.5% recruitment yield (ratio of participants to contacts). As the first large-scale genetic linkage study of African Americans, on a common disease, the challenges and successes of the recruitment process for the AAHPC Study should serve to inform future efforts to involve this population in similar studies.
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PMID:Recruitment experience in the first phase of the African American Hereditary Prostate Cancer (AAHPC) study. 1118 95

As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P=.00012], 1q42.2-43 [PCAP; LOD score 2.84, P=.0030], and 4q [LOD score 2.80, P=.00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P=.00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.
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PMID:Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. 1130 85


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