[Association of a positive family history with histopathology and clinical course in early-onset prostate cancer]. / Assoziation von familiärem Status mit Histologie und klinischem Verlauf beim frühen Prostatakarzinom.

BACKGROUND: In a large number of studies a positive family history is documented as one of the main risk factors for the development of prostate cancer. In a US population an association between early-onset prostate cancer among familial patients and a more differentiated tumour was shown. The aim of this study was to compare clinical parameters between sporadic and familial or hereditary patients with an age at diagnosis < or =55 years. MATERIAL AND METHODS: The clinical data of prostate cancer patients with an age at diagnosis < or =55 years and who were recruited between July 1999 and the end of June 2004 to the database "familial prostate cancer in Germany" were analysed. The following data were documented for all patients: PSA at diagnosis, histopathological stage, grading, Gleason score and progression-free survival. RESULTS: The clinical data of 685 patients could be completed: 222 (32.4%) had one first-degree relative with prostate cancer, 48 of whom (7.0%) were hereditary; 463 (67.6%) were sporadic. The median age at diagnosis in the hereditary patients was 51.6 (41-55) years, in the familial patients 51.1 (35-55) years and in the sporadic patients 52.0 (38-55) years. The median follow-up was 24 months in hereditary, 36 months in familial and 35 months in sporadic patients. An initial curative therapy with radical prostatectomy or radiotherapy/brachytherapy was planned in 657/685 (95.9%) of the patients. There were no clear differences regarding PSA at diagnosis, the postoperative parameters (organ-confined disease, lymph node involvement, Gleason score, grading) and the progression-free survival in sporadic and familial or hereditary patients. CONCLUSIONS: Patients with an age at diagnosis < or =55 years have a positive family history more often than all prostate cancer patients in Germany. No association could be shown between pathohistological stage or clinical course and a positive family history in patients with an age at diagnosis < or =55 years.

[Prospective evaluation of prostate cancer screening in men with a family history of the disease]. / Prospektive Evaluierung der Prostatakarzinomfrüherkennung bei Männern mit familiärer Disposition.

BACKGROUND: Family history is one of the strongest risk factors for prostate cancer. In this prospective study we evaluated the results of prostate cancer screening performed in healthy brothers of prostate cancer patients. The detection rate of prostate cancer and the positive predictive value of the examinations were determined. MATERIAL AND METHODS: The study population comprised 513 healthy men who were 38-75 years of age (median 62.0 years). Of these men, 268 having only one affected brother with prostate cancer were assigned to the sporadic group, and 245 probands having 2-10 affected relatives were assigned to the familial group. An abnormal PSA and/or a pathological digital rectal examination (DRE) was noted in 17.5% of familial (43/245) and 15.8% of sporadic probands (35/268). A biopsy of the prostate was performed in 60.5% of familial (26/43) and 71.4% of sporadic (25/35) men with pathological findings. RESULTS: Prostate cancer was found in 15 of 26 familial (57.7%) and 16 of 25 sporadic (64.0%) probands by prostate biopsy. The overall detection rate was 6.0% (31/513). CONCLUSION: Due to an increased prevalence the detection rate of prostate cancer and the positive predictive value of PSA and/or DRE are higher in men with a family history as expected in an unselected population. Our data suggest that in predisposed men prostate cancer screening should be recommended early. Furthermore an early indication for prostate biopsy is necessary. This recommendation should also be applied if only one first-degree relative has prostate cancer.

[Klippel-Trénaunay syndrome. A rare cause of recurrent macrohematuria: case report]. / Klippel-Trenaunay-Syndrom. Eine seltene Ursache für rezidivierende Makrohämaturie - kasuistische Falldarstellung.

A 37-year-old man with Klippel-Trénaunay syndrome presented with an episode of painless severe gross hematuria. Magnetic resonance imaging (MRI) revealed vessels of significant diameter in the bladder wall. Diagnostic imaging is mandatory in order to be aware of the extent of the lesion as the bleeding identified intraoperatively may only be the "tip of the iceberg." If conservative means fail, laser coagulation should be the treatment of choice.

Radiosensitivity detected by the micronucleus test is not generally increased in sporadic prostate cancer patients.

The micronucleus test (MNT) has shown increased micronuclei (MN) frequencies in BRCA associated and sporadic breast cancer patients, Ataxia telangiectasia and Nijmegen Breakage Syndrome patients, demonstrating a common cellular phenotype of increased radiosensitivity. Some genes, causative of these diseases, have also recently been associated with prostate cancer. In order to investigate if prostate cancer exhibits the cellular phenotype of increased radiosensitivity, we performed MNT analysis on 22 sporadic prostate cancer patients and 43 male controls. We determined the baseline MN frequency, in order to see in vivo chromosomal damage without radiation, and induced (after irradiation with 2 Gy) frequency of MN, both in binucleated cells (BNC) obtained from cultured peripheral blood lymphocytes. An automated image analysis system was used to score the MN employing two different classifiers (Classifier A and B) for detection of BNC. The mean baseline frequencies were 48/43 MN/1000 BNC (A/B) for the controls and 42/50 (A/B) for prostate cancer patients. The induced MN frequencies amounted to 107/111 MN/1000 BNC (A/B) for controls and 111/114 MN/1000 BNC (A/B) for prostate cancer patients. The obtained MN frequencies did not result in a statistically significant difference between unselected cases and controls. However, restricting the analysis to young patients (50-60 years, N = 7) and age-matched controls (N = 7) revealed marginally significant higher MN frequencies in patients. We conclude that increased radiosensitivity is not a property of prostate cancer patients in general.

Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene.

To date, germline mutations have been found in three candidate genes for hereditary prostate cancer: ELAC2 at 17p11, RNASEL at 1q25 and MSR1 at 8p22. RNASEL, encoding the 2',5'-oligoadenylate-dependant RNase L, seems to have rare mutations in different ethnicities, such as M1I in Afro-Americans, E265X in men of European descent and 471delAAAG in Ashkenazi Jews. In order to evaluate the relevance of RNASEL in the German population, we sequenced its open reading frame to determine the spectrum and frequency of germline mutations. The screen included 303 affected men from 136 Caucasian families, of which 45 met the criteria for hereditary prostate cancer. Variants were analysed using a family-based association test, and genotyped in an additional 227 sporadic prostate cancer patients and 207 controls. We identified only two sib pairs (1.4% of our families) cosegregating conspicuous RNASEL variants with prostate cancer: the nonsense mutation E265X, and a new amino-acid substitution (R400P) of unknown functional relevance. Both alleles were also found at low frequencies (1.4 and 0.5%, respectively) in controls. No significant association of polymorphisms (I97L, R462Q and D541E) was observed, neither in case-control analyses nor by family-based association tests. In contrast to previous reports, our study does not suggest that common variants (i.e. R462Q) modify disease risk. Our results are not consistent with a high penetrance of deleterious RNASEL mutations. Due to the low frequency of germline mutations present in our sample, RNASEL does not have a significant impact on prostate cancer susceptibility in the German population.

[Is the prostate cancer screening behaviour of men with familial predisposition predictable?]. / Ist das Vorsorgeverhalten bei Männern mit familiärer Prädisposition für ein Prostatakarzinom vorhersehbar?

Little is known about the motives of German men to attend or refuse preventive checkups for prostate cancer. The aims of this study were to investigate if in men with familial predisposition screening behaviours are influenced by epidemiological or clinical parameters of prostate cancer of their affected relatives. 476 probands with one and 312 probands with at least two affected relatives were advised in writing to have a PSA-test and DRE done at their local urologists. We evaluated if the response rate was correlated to the proband's age, to the number and the age of onset of their affected relatives and also to the clinical course of their disease. Our data implicate that in men with familial predisposition the acceptance of prostate cancer screening is influenced only by individual characteristics and personal attitude and not by factors within the family. To which extent the awareness of disease risk is modified by familial predisposition remains to be evaluated.

[Familial versus sporadic prostate cancer in the German population. Clinical and pathological characteristics in patients after radical prostatectomy]. / Familiäres versus sporadisches Prostatakarzinom in der deutschen Population. Klinische und pathologische Charakteristika bei Patienten nach radikaler Prostatektomie.

Family history is one of the strongest epidemiological risk factors for the development of prostate cancer. The impact on the clinical presentation and prognosis, however, is controversial. In the present study, we analyzed 464 familial and 492 sporadic prostate cancer patients following radical prostatectomy. The average age at onset was 62.1 years in the familial group and 64.2 years in the sporadic controls (p<0.001). The screening attitude, DRE findings and the PSA values at diagnosis the pT- and pN-stages, and the tumor grade did not differ between both groups. With a median follow-up of 3.3 years, the 5- and 10-year progression-free survival rates were 76.2% and 56.5% in familial and 70.8% and 55.5% in sporadic patients, respectively (n.s.). A multiple logistic regression analysis revealed that family history did not have an influence on disease recurrence. In our population there was no association between a familial predisposition and clinical features or clinical course of the disease. Whether hereditary prostate cancer is distinct from sporadic forms cannot be determined before the underlying genetic alterations are identified.

Association between the clinical presentation and epidemiological features of familial prostate cancer in patients selected for radical prostatectomy.

OBJECTIVE: We evaluated if epidemiological features of familial prostate cancer are associated with certain clinical or histopathological characteristics of the disease. METHODS: 463 German patients with familial prostate cancer who underwent radical prostatectomy were stratified according to several epidemiological criteria: (1). the apparent mode of disease transmission, (2). the average age of onset and (3). number of affected relatives/family, (4). whether or not they met the Johns Hopkins criteria of hereditary prostate cancer. The variables analysed included the Prostate Specific Antigen (PSA) and the digital rectal examination at diagnosis, histopathological characteristics of the prostatectomy specimen and relapse free 5-year survival rates. These characteristics were compared within the subsets of familial patients and compared to 492 control patients with sporadic prostate cancer. RESULTS: Age of onset was the only clinical parameter differentiating familial and sporadic prostate cancer. Otherwise there was no association between epidemiological features of familial predisposition and the clinical presentation or outcome of the disease. CONCLUSIONS: Familial and sporadic prostate cancer seem to be the same disease. Alternatively it may be concluded that the common epidemiological features of familial prostate cancer are not useful to tell tumours that are based on inherited susceptibility apart from those that are not. Whether hereditary prostate cancer is clinically distinct from sporadic forms cannot be determined before the underlying genetic alterations are identified.

A candidate gene approach within the susceptibility region PCaP on 1q42.2-43 excludes deleterious mutations of the PCTA-1 gene to be responsible for hereditary prostate cancer.

OBJECTIVE: The Prostate Carcinoma Tumor Antigen-1 (PCTA-1) is located at the prostate cancer susceptibility locus on chromosome 1q42.2-43 (PCaP). In this candidate gene approach, we searched for deleterious mutations within the PCTA-1 gene and its promoter. MATERIALS AND METHODS: Seventy-seven familial prostate cancer cases from 36 German and French pedigrees were screened for germline mutations in the PCTA-1 gene using enzymatic mutation detection (EMD). Putative missense mutations were genotyped by RPLP and ddNTP primer extension assays in 88 controls to assess allele frequencies and haplotypes. RESULTS: Several sequence variants were found but none of the findings indicated a deleterious mutation. Three affected brothers showed an intronic variation, which may interfere with correct splicing. Four non-conservative SNPs were characterized, coding for the amino acid alterations Y19F, C36R, V56M and S184R. All exchanges were found in controls with common allelic frequencies of at least 28%. Haplotype definition including six SNPs within the PCTA-1 gene revealed a complete linkage disequilibrium. Low haplotype diversity leads to a predominance of only two peptide variants of the PCTA-1 protein, coded by 95% of all chromosomes. CONCLUSIONS: PCTA-1 is not a classical high risk gene with deleterious mutations predisposing to hereditary prostate cancer. Its contribution to prostate cancer susceptibility as a low risk factor in sporadic disease has to be assessed in larger samples by association studies.

[Familial prostate carcinoma in Germany]. / Das familiäre Prostatakarzinom in Deutschland.

Epidemiologic studies have shown that hereditary forms account for approximately 10% of all prostate cancers. The identification of several susceptibility loci harboring predisposing genes indicates the genetic heterogeneity of prostate cancer. The conflicting results of different linkage analyses may be explained by a varying contribution of each locus within different family collections and reflect differences of allele frequencies across different populations. In the present study we recorded the incidence of familial prostate cancer in Germany and performed descriptive analysis of the epidemiological data. In spite of a significant ascertainment bias, only 19% of all prostate cancers were familial. In 94% of families there were three affected relatives at most. Large prostate cancer families with at least five affected persons were rare (2%). Descriptive analysis revealed that only 42% of all pedigrees followed an autosomal-dominant pattern of transmission; the other pedigrees showed an X-chromosomal or recessive mode of inheritance. These data confirm the genetic heterogeneity of hereditary prostate cancer and imply that previously published epidemiological data cannot be transferred to the German population.

[Preventing prostate carcinoma in men with familial disposition]. / Prostatakarzinomvorsorge bei Männern mit familiärer Disposition.

A family history is one of the strongest risk factors for prostate cancer (PC). We evaluated the detection rate of PC in relatives of 119 German PC families that took part in ongoing linkage analyses. Brothers of patients with sporadic prostate cancer aged < 55 years at onset were included as well. Responses were received from 120/196 (61.2%) individuals of the familial and 67/120 (55.8%) of the sporadic group. Findings (DRE, TRUS, PSA) were more often suspicious for carcinoma in the PC families. Prostate cancer was diagnosed in 6 (5.0%) and 2 (2.99%) participants of the familial and the sporadic group, respectively. These detection rates tended to be higher than that of an age-matched subgroup of an unselected population in other European screening studies. The most important risk factor for the diagnosis of PC was a low average age at onset within the family. These data imply that prostate cancer screening in the high-risk group of men with familial predisposition cannot be assessed by population-based studies and should be evaluated separately.

[Genetic analysis of familial prostatic cancer: localization of a gene predisposing to prostatic cancer (PCaP) on chromosome 1q 42.2-43]. / Analyse génétique du cancer de la prostate familial: localisation d'un gène prédisposant au cancer de la prostate (PCaP) sur le chromosome 1q 42.2-43.

OBJECTIVES: To conduct genetic linkage analysis in order to localize predisposition genes for hereditary prostate cancer (CaP), as various epidemiological studies have demonstrated a family aggregation in 15 to 25% of cases, and the development of hereditary forms in 5 to 10% of cases of CaP. MATERIAL AND METHODS: A genetic study on 47 French and German families included 122 patients and 72 subjects considered to be healthy after PSA assay. This study was conducted by linkage analysis of 364 microsatellite markers distributed throughout the genome (on average every 10 cM). RESULTS: Parametric and nonparametric linkage analysis identified a locus on chromosome 1q 42.2-43, which could be with a gene predisposing to CaP (called PCaP). The primary site was confirmed by several markers, using 3 different genetic models. The maximum LOD score (probability of linkage between the locus and the disease) on two-point analysis was 2.7 for the D1S2785 marker. Parametric and nonparametric multipoint analysis provided an HLOD score and an NPL score of 2.2 and 3.1, respectively (with P = 0.001). Heterogeneity analysis with calculations of LOD scores by multipoint analysis estimated that up to 50% of hereditary CaPs were related to this locus, with a heterogeneity probability of 157/1. Analysis of a subgroup of 9/47 families characterized by early onset CaP (before the age of 60 years) confirmed the very high probability of localization of a predisposition gene at locus 1q42.2-43 for these families (multipoint LOD score and NPL score of 3.31 and 3.32, respectively; with P = 0.001). CONCLUSION: The identification of predisposition genes will eventually allow identification within certain families of those subjects who have inherited the genetic abnormality and who therefore present a high risk of CaP. It will then be possible to perform targeted screening of CaP in order to diagnose CaP as early as possible.

(CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population.

Alleles of the CAG and the GGC repeat in the first exon of the human androgen receptor (AR) gene have been shown to be associated with the risk of (advanced) prostate cancer. These studies had been carried out in the United States. We have analysed these polymorphisms in a French-German collection of 105 controls, 132 sporadic cases, and a sample of prostate cancer families comprising 85 affected and 46 not affected family members. The allele distributions were very similar in all four groups and chi square statistics on contingency tables did not detect any significant differences. The relative risk (odds ratio, OR) were calculated using logistic regression and did not reach significance despite sufficient numbers of patients and controls. Typical results were OR = 1.007; 95% Confidence Interval (CI) 0.97-1.1, P = 0.87 for CAG as continuous variable and OR = 1.2 (95% CI 0.7-2.0), P = 0.47 for CAG classes < 22 and > = 22 repeats. Similar results were obtained for subgroups defined by age or Gleason score. We conclude that these polymorphisms can not be used as predictive parameters for prostate cancer in the French or German population.

Detailed marker chromosome analysis in cell line U-BLC1, established from transitional-cell carcinoma of the bladder.

A permanent cell line, U-BLC1, was established from a primary transitional-cell carcinoma, TCC, of the urinary bladder. Karyotype analysis showed the line to be highly aberrant, with a near-triploid chromosome number of 68 to 73. Comparative genomic hybridization revealed some distinct differences between the primary tumor and the established cell line. Karyotype analysis showed 3 marker chromosomes with homogeneously staining regions, HSRs, in the cell line. The HSRs were isolated by microdissection and the microdissection probes were hybridized to normal metaphase chromosomes. The HSRs contain sequences known to be frequently involved in amplification in transitional-cell carcinoma of the bladder, 6p22, 7p11-p12, 9p23-pter, and one region not yet reported to be amplified in primary TCC of the bladder, 1p31-p32. A candidate-gene approach showed that in the region 7p11-p12 the EGFR locus is amplified and highly expressed.

The ileal neobladder: complications and functional results in 363 patients after 11 years of followup.

PURPOSE: Since 1986 orthotopic lower urinary tract reconstruction using the ileal neobladder has been our diversion of choice in patients of both sexes undergoing cystectomy. We report on experience and functional results of the first 363 men 11 years after this procedure. MATERIALS AND METHODS: Complications were assessed, tabulated, subdivided into early (3 months or less postoperatively) and late types, and further categorized with respect to relationship to neobladder construction. Continence and voiding pattern were individually evaluated via a detailed patient questionnaire. RESULTS: Perioperative death occurred in 11 patients (3%). Neobladder related early and late complications occurred in 56 (15.4%) and 85 (23.4%) of the 363 patients, respectively. Neobladder related early and late abdominal reoperation rates were 0.3 and 4.4%, respectively. Perioperative neobladder unrelated early complications were observed in 122 patients (33.6%) and 44 (12.1%) required operative treatment. Late postoperative complications unrelated to the neobladder occurred in 45 patients (12.4%) and 19 required open surgical revision. Of 290 evaluable patients 96.1% void spontaneously, 3.9% perform clean intermittent catheterization in some form and 1.7% perform regular intermittent catheterization. Daytime and nighttime continence was reported as good by 95.9% and satisfactory by 95% of the patients. Unacceptable daytime continence requiring more than 1 pad per day occurred in only 4.1% of the patients and only 5% are wetting more than 1 pad a night. CONCLUSIONS: The ileal neobladder produces good functional results and can be constructed with acceptable complications. Our data suggest that although it is not a complication-free procedure, we advocate its use when possible.

Vitamin D receptor polymorphisms as markers in prostate cancer.

Polymorphisms in the vitamin D receptor (VDR) gene have been analyzed in several studies for an association with prostate cancer (PCA) and odds ratios (OR) > or = 3 have been observed in study populations from North America. We studied three polymorphisms in the VDR gene (poly-A microsatellite, TaqI and FokI RFLPs) in 105 controls and 132 sporadic PCA cases from France and in a collection of families from Germany and France. The polymorphisms near the 3' end of the gene were in linkage disequilibrium with an almost complete coincidence of the short poly-A alleles and t (presence of the restriction site) of the TaqI polymorphism, (contingency tables, P<0.0001). An association was found by logistic regression for the poly-A between PCA and the heterozygous genotype (S/L; S < 17, L > or = 17, OR=0.44, 95% confidence interval, CI=0.198-0.966, P=0.041). OR was lower in patients < or = 70 years old and patients with a Gleason score > or = 6. The Tt genotype of the TaqI RFLP also showed an association with PCA (OR=0.5, CI=0.27-0.92, P=0.026). This association was also stronger for patients < or = 70 years old (OR=0.31, CI=0.15-0.63, P=0.001). The risk alleles were S and t alleles as indicated by the OR of the homozygotes, although these were not significant. The FokI RFLP at the 5' end of the gene did not reveal any association (P>0.7). While some association studies differ between Europe and North America, our present findings with the VDR gene agree with those from North America, indicating a weak but general role of the VDR in PCA susceptibility.

Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q.

The cascade of genetic alterations leading to malignant transformation has been described for adenocarcinoma of the colon but is not established for other common tumor entities. In the present study, different stages of transitional cell carcinoma (TCC) of the bladder are analyzed by comparative genomic hybridization. A dynamic pattern of the chromosomal changes during tumor progression is described. Deletion of chromosome arm 9q is the earliest genetic alteration in pTa tumors. In stage pT1 carcinomas, losses of 9q, 9p, and 11p and gain of 1q and 8q are the most common. In addition to the changes specific for earlier stages, gain of 5p and 20q becomes prominent in carcinomas stage > or =pT2. Association analysis reveals a remarkable cooccurrence of 9p deletion with gain of 5p and 20q in > or =pT2 tumors. In order to determine more precisely the size of the amplified segment and the degree of amplification on chromosome arm 8q in stage pT1 tumors, this region was analyzed by semiquantitative PCR using polymorphic microsatellite markers. These studies revealed an up to 13-fold amplification. The common region of amplification could be narrowed down to 8q22.3 and between GAAT1A4 and D8S1834 (about 7 cM).

Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43.

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.