Biomedical subjects

Kathleen E Wiley

Publications and source records attributed to Kathleen E Wiley.

11 recordsLinked to original sources

PubMed2006

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

Black or African American↗

PubMed2006

Germline ATBF1 mutations and prostate cancer risk.

BACKGROUND: ATBF1 has been recently identified as a candidate prostate tumor suppressor gene. In addition to more unique mutations, two somatic mutations (shortening of a polypyrimidine tract [Poly(T)n] and a deletion beginning at codon 3381 (3381del)) were each observed in multiple prostate cancer samples and both appear to have an impact on ATBF1 gene function and expression. METHODS: We assayed two recurrent sequence variants in germline DNA from prostate cancer cases and controls, and examined whether carriers of these variants are at increased risk for prostate cancer. RESULTS: We found Poly(T)n variants in both normal and matched tumor DNA samples from multiple patients, indicating a germline origin in each case. Genotyping germline DNA samples indicated that 3381del was significantly associated with prostate cancer risk among sporadic cases (P = 0.03), but not among men with hereditary disease. CONCLUSIONS: Our study indicates that the germline 3381del allele may influence prostate cancer susceptibility.

Alleles↗

PubMed2005

Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect.

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease. Therefore, modeling gene-gene interactions in linkage analysis may improve the power to detect chromosomal regions harboring these disease susceptibility genes. In this study, we systematically screened for prostate cancer linkage by modeling two-locus gene-gene interactions for all possible pairs of loci across the genome in 426 prostate cancer families from Johns Hopkins Hospital, University of Michigan, University of Umeå, and University of Tampere. We found suggestive evidence for an epistatic interaction for six sets of loci (target chromosome-wide/reference marker-specific P< or =0.0001). Evidence for these interactions was found in two independent subsets from within the 426 families. While the validity of these results requires confirmation from independent studies and the identification of the specific genes underlying this linkage evidence, our approach of systematically assessing gene-gene interactions across the entire genome represents a promising alternative approach for gene identification for prostate cancer.

Aged↗

PubMed2005

A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Aged↗

PubMed2005

A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.

Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.

Alleles↗

PubMed2004

Mutational analysis of PINX1 in hereditary prostate cancer.

BACKGROUND: Telomerase activity is increased in most tumors. PinX1 has recently been identified as a critical component in regulating telomerase activity. The PinX1 gene is located within chromosomal region 8p22-23, a region associated with LOH and potentially linked to increased prostate cancer risk. METHODS: PINX1 was re-sequenced in 159 hereditary prostate cancer (HPC) probands. Four non-synonymous coding variants were genotyped in 159 HPC families. RESULTS: Thirty-nine polymorphisms were identified in the HPC screening panel. Ten coding polymorphisms were identified, seven (Gln50His, Leu91Met, Gln206His, Arg215Ile, Thr220Ala, Ser254Cys, and Glu414Ala) of which were non-synonymous. The most common variants Thr220Ala and Ser254Cys were not significantly over-transmitted from affected parent to affected offspring. CONCLUSIONS: Based on these results, we conclude that PINX1 is not a major factor for HPC risk.

Cell Cycle Proteins↗

PubMed2004

Combined genome-wide scan for prostate cancer susceptibility genes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.

Biomarkers, Tumor↗

PubMed2003

Familial aggregation of bothersome benign prostatic hyperplasia symptoms.

OBJECTIVES: To evaluate familial aggregation and the mode of inheritance of bothersome benign prostatic hyperplasia (BPH). METHODS: During an extension of the North American Finasteride Trial, 301 of 895 patients and 158 spousal controls completed a family history questionnaire. Segregation analysis was performed to examine the mode of inheritance in first-degree relatives of the 301 probands. RESULTS: The lifetime cumulative probability of bothersome BPH was similar in relatives of those with BPH (0.35; 95% confidence interval [CI] 0.28 to 0.44) and spousal controls (0.36; 95% CI 0.22 to 0.56), but the age of onset was significantly earlier in relatives of cases than controls (P = 0.001). Fathers of those with BPH had a significantly elevated risk of bothersome BPH (unadjusted odds ratio [OR] 2.1; 95% CI 1.2 to 3.8) and brothers had a significantly elevated risk of both bothersome BPH (OR 3.5; 95% CI 1.7 to 7.3) and transurethral resection of the prostate (OR 3.6; 95% CI 1.4 to 8.8). After adjusting for family size, the risk of bothersome BPH increased approximately twofold with each additional affected first-degree relative (0 relatives, OR 1.0; 1 relative, OR 1.7; 2 relatives, OR 4.7). Segregation analysis suggested a rare autosomal codominant allele (frequency 0.0004). CONCLUSIONS: These findings confirm previous findings that family history and early age of onset are associated with an increased risk of BPH and that the most likely mode of inheritance is autosomal dominant or codominant. Bothersome BPH appears to have a weaker genetic component than more restrictive definitions of hereditary BPH. Thus, linkage studies are more likely to be successful if they focus on stricter definitions of hereditary BPH (eg, early onset, large volume, strong family history) rather than symptomatic or clinical BPH.

Adult↗

PubMed2002

Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.

Case-Control Studies↗

PubMed2002

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Aged↗

PubMed2002

Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.

The 8p22 through p23 region has been identified as a potential site for genes associated with prostate cancer. The gene LZTS1 has been mapped to the 8p22 through p23 region and identified as a potential tumor suppressor based on loss of heterozygosity studies using primary esophageal tumors. Sequence analysis of mRNA from various tumors has revealed multiple mutations and aberrant mRNA transcripts. The most recent report associates LZTS1 function with stabilization of p34(cdc2) during the late S-G2/M stage of mitosis, affecting normal cell growth. In this study, a detailed DNA sequence analysis of LZTS1 was performed in a screening panel consisting of sporadic and hereditary prostate cancer (HPC) cases and unaffected controls. Twenty-four SNP, 15 of which were novel, were identified in germline DNA. Four coding SNP were identified. Eleven informative SNP were genotyped in 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Four of these SNP were statistically significant for association with prostate cancer (P < or = 0.04). These results add evidence supporting a role of LZTS1 in prostate cancer risk.

Base Sequence↗