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Patrick C Walsh

Publications and source records attributed to Patrick C Walsh.

At least 19 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↗
PubMed2006

Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.

NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper.

Amino Acid Sequence↗
PubMed2006

Pathological outcomes and biochemical progression in men with T1c prostate cancer undergoing radical prostatectomy with prostate specific antigen 2.6 to 4.0 vs 4.1 to 6.0 ng/ml.

PURPOSE: Recent studies have suggested that the cut point for recommending prostate biopsy among men with a normal digital rectal examination should be greater than 2.5 ng/ml as opposed to the more traditional greater than 4.0 ng/ml. We compared outcomes between men with clinical stage T1c disease undergoing radical prostatectomy who had a low vs slightly increased prostate specific antigen. MATERIALS AND METHODS: The study population consisted of 2,896 men treated with radical prostatectomy between 1985 and 2004 at a tertiary care referral center with clinical stage T1c disease and a pre-biopsy prostate specific antigen between 2.6 and 6.0 ng/ml. Using multivariate analysis we evaluated the association between pre-biopsy prostate specific antigen 2.6 to 4.0 ng/ml (784) vs 4.1 to 6.0 ng/ml (2,112), and pathological outcomes and biochemical progression. RESULTS: After adjusting for multiple clinical and pathological characteristics, lower preoperative serum prostate specific antigen values were associated with decreased odds of Gleason score 7 or greater in the surgical specimen (p = 0.004), positive surgical margins (p = 0.02) and extraprostatic extension (p = 0.001). There was no significant association between these preoperative prostate specific antigen groups and odds of seminal vesicle invasion (p = 0.47) or lymph node metastasis (p = 0.90). Among the 1,534 men with followup information available there was a trend for increased risk of biochemical progression associated with a higher preoperative prostate specific antigen, although this trend did not reach statistical significance (relative risk 1.48, 95% CI 0.69-3.19, p = 0.31). CONCLUSIONS: In the current study of men with clinical stage T1c treated with radical prostatectomy a lower preoperative prostate specific antigen was associated with significantly more favorable pathological findings. Whether this degree of improved outcomes justifies the limitations associated with decreasing the prostate specific antigen cut point (eg increased biopsies performed and diagnosis of insignificant cancers) remains to be determined.

Disease Progression↗
PubMed2006

Black race does not independently predict adverse outcome following radical retropubic prostatectomy at a tertiary referral center.

PURPOSE: There is controversy in the literature as to whether black race is associated with poorer oncological outcomes among men undergoing radical prostatectomy for clinically localized prostate cancer. To address this issue we examined the outcomes of a cohort of black and white men treated by multiple surgeons at our institution. MATERIALS AND METHODS: The study population consisted of 4,962 white and 326 black men treated with anatomical radical retropubic prostatectomy between 1988 and 2004 by 10 different surgeons at the Johns Hopkins Hospital, a tertiary care referral center. We evaluated the association between race and adverse pathological features, and biochemical progression. RESULTS: Black men had significantly higher preoperative serum prostate specific antigen (mean 7.2 vs 6.0 ng/ml, p <0.001), body mass index (median 27.4 vs 26.3 kg/m, p <0.001) and incidence of higher grade disease (Gleason sum 4 + 3 or greater) on prostate biopsy (17% vs 14%, p = 0.011). After adjustment for multiple clinical variables there was no statistically significant association between race and the adverse pathological characteristics of high grade disease, positive surgical margins, extraprostatic extension or seminal vesicle invasion. Black race was associated with a significantly increased risk of biochemical progression on univariate analysis (HR 1.52, 95% CI 1.16-2.00, p = 0.002). However, after adjusting for clinical and pathological characteristics, black race was not an independent predictor of biochemical progression (HR 1.09, 95% CI 0.81-1.45, p = 0.578). CONCLUSIONS: Black men were more likely to be obese and present with adverse preoperative clinical features at a younger age, and have a higher rate of biochemical progression. However, on multivariate analysis black race was not an independent predictor of adverse pathological outcome or biochemical recurrence. Further efforts are needed to detect prostate cancer earlier among black men.

Adenocarcinoma↗
PubMed2006

Relationship between primary Gleason pattern on needle biopsy and clinicopathologic outcomes among men with Gleason score 7 adenocarcinoma of the prostate.

OBJECTIVES: To examine the relationship among needle biopsy primary grade, prostatectomy grade, and postprostatectomy biochemical recurrence among men with Gleason score 7 disease. METHODS: We identified 320 men with Gleason score 7 tumors on prostate biopsy treated with radical prostatectomy between 1991 and 2001 by a single surgeon. None of these patients had received neoadjuvant or adjuvant hormonal therapy or radiotherapy. The chi-square test and Kaplan-Meier method were used to evaluate the correlation among biopsy Gleason score, prostatectomy Gleason score, and biochemical recurrence. RESULTS: A total of 252 (79%) and 68 (21%) men had primary Gleason pattern 3 and 4 identified on needle biopsy, respectively. Of the patients with Gleason pattern 3 + 4 tumors on biopsy, 24% were upgraded to primary pattern 4 or more on final pathologic analysis. Of the patients with Gleason pattern 4 + 3 tumors on biopsy, 47% were downgraded to primary pattern 3 or less on final pathologic analysis. The actuarial risk of biochemical prostate-specific antigen recurrence was significantly lower among patients with Gleason pattern 4 + 3 on biopsy, if the prostatectomy Gleason score was downgraded to 3 + 4 or less (P = 0.03). CONCLUSIONS: Approximately 47% of men with a diagnosis of Gleason pattern 4 + 3 on needle biopsy are downgraded at radical prostatectomy and will have biochemical prostate-specific antigen recurrence-free outcomes similar to patients originally diagnosed with Gleason pattern 3 + 4 adenocarcinoma. This group of patients may benefit from definitive treatment such as radical prostatectomy for management of their disease.

Adenocarcinoma↗
PubMed2006

Concordance rates and modifiable risk factors for lower urinary tract symptoms in twins.

INTRODUCTION: Lower urinary tract symptoms, which are common in older men, are thought to be determined genetically and by modifiable environmental risk factors. We examined the contribution of these 2 etiologic components in a cohort of U.S. twins. METHODS: In 1998, a questionnaire that assessed lower urinary tract symptoms, weight, height, alcohol consumption, cigarette smoking, and physical activity was sent out to members of the National Academy of Science-National Research Council Twins Registry. We analyzed 1,723 complete twin pairs with information on lower urinary tract symptoms and zygosity and who did not have a previous diagnosis of prostate cancer. We calculated concordance rates of categories of the International Prostate Symptom Score in monozygotic (MZ) and dizygotic (DZ) twins. Generalized estimating equations were used to calculate the odds ratio of having high-moderate/severe lower urinary tract symptoms. RESULTS: Concordance rates were higher in MZ than in DZ twins with concordance rate ratios of 2.2 and 6.9 depending on the specificity of definition of symptoms. Genetic factors contributed 72% to the risk of high-moderate/severe lower urinary tract symptoms. Taking into account correlated individuals, we observed high odds of lower urinary tract symptoms in obese men compared with lean men (odds ratio = 1.91; 95% confidence interval = 1.16-3.15 comparing first versus fourth quartile). Cigarette smoking was not associated with lower urinary tract symptoms, but alcohol consumption was positively associated. Men who were more physically active tended to have lower odds of lower urinary tract symptoms compared with less active men (0.62; 0.36-1.08). CONCLUSION: The findings indicate a strong genetic component of lower urinary tract symptoms, but also support previous studies that modifiable environmental risk factors are associated with this condition.

Aged↗
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

Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease.

BACKGROUND: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer. METHODS: We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer. RESULTS: Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p. CONCLUSIONS: Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.

Family Health↗
PubMed2005

Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy.

CONTEXT: The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed. OBJECTIVES: To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years). MAIN OUTCOME MEASURE: Prostate cancer-specific mortality. RESULTS: Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs > or =15.0 months), pathological Gleason score (< or =7 vs 8-10), and time from surgery to biochemical recurrence (< or =3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence. CONCLUSION: Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.

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

Stronger association between obesity and biochemical progression after radical prostatectomy among men treated in the last 10 years.

BACKGROUND: Prior prospective cohort studies found that obesity was associated with increased risk of prostate cancer death. However, in the last 20 years dramatic changes in both the extent of obesity and prostate cancer screening and treatment have occurred. Whether the association between obesity and aggressive disease has changed as a result of these temporal changes is unclear. METHODS: The study population consisted of 2,832 men treated by anatomic radical retropubic prostatectomy between 1985 and 2004 by a single surgeon. We evaluated the associations of obesity (body mass index > or =30 kg/m(2))with tumor stage and grade using logistic regression and with biochemical progression using Cox proportional hazards regression. We examined whether these associations have changed over the last 20 years. RESULTS: On multivariable analysis, the strength of the positive association between obesity and high-grade disease increased over time whereas the strength of the positive association between obesity and positive surgical margins decreased over time. The strength of the positive association between obesity and extraprostatic extension fluctuated over time, although the strongest and only statistically significant association was among men treated since 2000. The association between obesity and biochemical progression was strongest among men treated since 1995 (relative risk, 1.90; 95% confidence interval, 1.09-3.30; P = 0.02). CONCLUSIONS: In the current study, with the exception of positive surgical margins, the positive association between obesity and high-grade disease, advanced stage, and biochemical progression after radical retropubic prostatectomy was in general strongest among men treated in the last 10 years. The reasons for these findings are not clear, although factors possibly related to prostate-specific antigen-based screening and/or other temporal changes in prostate cancer diagnosis and treatment may play a role.

Body Mass Index↗
PubMed2005

Evidence for a general cancer susceptibility locus at 3p24 in families with hereditary prostate cancer.

To identify genes that generally increase the risk of cancer, we performed a systematic search throughout the genome in 188 families primarily ascertained for prostate cancer but which also included individuals with other cancers. We observed significant evidence for linkage between susceptibility to all cancers and markers at 3p24, with a peak HLOD of 3.08 (P=0.0002). Compared to families with less than three other cancers and prostate cancer only, evidence for linkage at this region was stronger among families with at least three other cancers. This is the first reported example of a genome-wide search for general cancer susceptibility genes among hereditary prostate cancer families.

Chromosomes, Human, Pair 3↗
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↗
PubMed2005

Efficacy of continuous local anesthetic infusion for postoperative pain after radical retropubic prostatectomy.

OBJECTIVES: To determine whether a subfascial continuous infusion of local anesthetic in patients undergoing radical retropubic prostatectomy would result in a reduction in postoperative opioid requirements and an improvement in pain scores. METHODS: This was a prospective, double-blind, placebo-controlled, randomized trial in patients undergoing elective radical retropubic prostatectomy. A small catheter was placed subfascially at the end of surgery and attached to an elastomeric pump that administered either 0.5% bupivacaine or normal saline into the wound at a rate of 2 mL/hr until discharge on postoperative day 3. The outcomes assessed included the dosage of hydromorphone used by a patient-controlled analgesic system, a visual analog scale (VAS) for pain at rest and with activity, a VAS of nausea, and length of hospital stay. RESULTS: A total of 100 patients were successfully randomized, with all patients completing the protocol. No differences were found between the groups with regard to VAS pain at rest, VAS pain with activity, intravenous or oral analgesic consumption, or VAS nausea scores. CONCLUSIONS: Continuous subfascial infusion of local anesthetic did not result in a postoperative reduction in opioid requirements or an improvement in pain scores in patients undergoing radical retropubic prostatectomy.

Anesthetics, Local↗