Early-onset hereditary prostate cancer is not associated with specific clinical and biological features.

BACKGROUND: Familial prostate cancer (CaP) accounts for 15-20% of all CaP, and hereditary CaP for 5-10% of patients. Few data are available concerning their clinical and biological features. METHODS: We compared diagnostic modalities, age, clinical stage, PSA, and tumor grade at diagnosis in CaP patients according to familial CaP profile: hereditary (HR) (> or =3 CaP), familial nonhereditary (FNH) (= 2 CaP), and sporadic CaP. Only cases diagnosed after January 1, 1987 (PSA-available period) were included. We considered as informative sporadic (IS) cases those probands with 2+ nonaffected brothers at least 50 years old. Finally, 267 CaP (230 probands and 37 affected brothers) were studied. RESULTS: In multivariate analysis, the only specific parameter significantly associated with HR and FNH CaP was early age at diagnosis; mean ages were 65.3 years (HR), 67 years (FNH), and 70.9 years (IS) (P < 0. 0001). No significant difference was observed concerning clinical stage, PSA, and tumor grade. In addition, diagnostic modalities were similar in the three groups. CONCLUSIONS: Our data confirm the occurrence of early-onset CaP in hereditary families. Although the clinical and biological presentation of HR CaP remains controversial, the lack of specific features observed in our study leads us to conclude that there is no difference in the aggressiveness of the disease in hereditary compared to sporadic CaP.

Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives.

Genetic predisposition accounts for >/=10% of all cancer of the prostate (CaP) and is therefore considered a major risk factor, together with age and ethnic origin. Several epidemiological studies have suggested that familial clustering of CaP may be associated with an increased frequency of breast and other cancers among relatives. In order to correlate the incidence of CaP with prevalence of breast and other cancers, we have performed uni- and multi-variate analyses on 691 complete pedigrees including probands, who were consecutive patients with confirmed CaP treated in three French urological departments. We have shown a significantly higher risk (RR = 2.3, p = 0.01) to develop breast cancer in families with multiple than in those with a single CaP. Risk of observing other types of cancer within these families was not significant. We then calculated the breast cancer risk in early onset prostate cancer families, and observed a relative risk that is even more significant (RR = 5.5, p = 0.002). Furthermore, the risk was >30 times that a proband's mother have breast cancer if CaP occurred below 55 years of age, rather than after 75 years (p = 0.003). This study has therefore shown for the first time, the relatively high penetrance for breast cancer in relatives of early onset CaP patients.

[Epidemiology of familial prostatic cancer: 4-year assessment of French studies]. / Epidémiologie du cancer de la prostate familial: bilan à 4 ans des études françaises.

OBJECTIVES: (1) To determine the frequency of familial (at least 2 cases) and hereditary forms of prostate cancer (CaP), (2) to define the results according to the patient's age at diagnosis, as various epidemiological studies have demonstrated a possible familial aggregation of CaP in about 15 to 25% of cases. Carter's familial segregation study (P.N.A.S. 1992, 89, 3367-71) showed that a genetic predisposition, with autosomal dominant transmission, could be responsible for 9% of all cases of prostate cancer. MATERIAL AND METHODS: We conducted a systematic genealogy study of patients suffering from newly diagnosed CaP or followed for known CaP in 3 French urological centres, by means of questionnaires completed by the patients. Subsequently, a national collection of families with at least 2 cases of CaP identified families with hereditary forms of CaP. Hereditary cases were considered to be those presenting at least: one CaP in three 1st degree relatives, or 3 cases over 3 generations in the same branch of the family (paternal or maternal), or finally 2 early cases before the age of 55 years. Statistical analysis used the univariate logistic regression test between family status and the medical centre or the patient's age at diagnosis. RESULTS: From July 1994 onwards, we included 801 patients (all stages combined) in the systematic study and 110 patients (13.7%) were excluded (refusal to participate, advanced age). For 691 of the families studied (Brest: 225, Nancy: 249, Paris St Louis: 217), we observed 32 (14.2%), 29 (11.6%), 37 (17.1%) of familial forms (mean: 14.2%) and 11 (4.9%), 6 (2.4%), 8 (3.7%) of hereditary forms (mean: 3.6%), respectively (no significant differences between centres). Analysis of the results according to age at diagnosis of CaP also showed a higher incidence of familial (significant difference) and hereditary forms (limit of significance) for CaP occurring at a younger age (before 65 years). The national collection collected a total of 624 familial forms of CaP, including 236 (37.8%) cases of hereditary forms; 115 families were informative for the genetic linkage study. CONCLUSION: These results confirm the data of earlier studies, revealing about 15 to 25% of familial forms of CaP and 5 to 10% of hereditary forms. Similarly, the systematic study confirmed the earlier onset of CaP in patients with a genetic predisposition. These data therefore encourage systematic questioning of patients for a family history of CaP in order to propose targeted screening of high-risk subjects in the families concerned and to intensify identification of hereditary forms in order to investigate the genes involved.

[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.

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.

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.

Binding sites of fluorescent probes on human serum albumin.

Human serum albumin is known to have two major and selective drug binding sites, termed sites I and II. The fluorescent probes, dansylamide and dansylsarcosine selectively interact with sites I and II, respectively. However, the binding site of the fluorescent probe dansylglycine on human serum albumin is not clear from the literature. This study investigated whether dansylglycine interacts tightly with site I or II. Spectrofluorimetric titrations (quenching and complex) and circular dichroism measurements were performed to determine the binding characteristics of dansylglycine to human serum albumin. Modification in probe fluorescence was described by fluorescence titrations to be a result of competitive displacement by ligands. The pattern of displacement of this probe by several ligands whose primary binding sites are exactly known, enabled the identification of its specific binding site. The fluorescence of dansylglycine is only extensively changed when ligands of site II are added, suggesting that it strongly interacts with the benzodiazepine/indole binding site on human serum albumin.

Anti-inflammatory properties of IL-1 in carrageenan-induced paw oedema.

To evaluate any inhibitory effect of a single dose of human recombinant interleukin-1 beta (hrIL-1 beta) on the severity of carrageenan-induced oedema in rats (a commonly used model of acute inflammation), we first injected 0.1 ml of carrageenan (0.2%, 0.5%, or 2%) to induce mild, moderate, or severe inflammation, respectively into the right rear footpad. Then we promptly injected the interleukin (0.02, 0.2, or 2 micrograms) subcutaneously into the flank. The initial rapid increase in volume of the injected paw (within 2 h of the subplantar injection) was independent of the dose of carrageenan, whereas the increase in volume by 6 to 10 h was dose-dependent. All doses of HrIL-1 beta inhibited the carrageenan-induced swelling at the 6th hour. In the moderate and severe carrageenan-induced oedemas, the higher dose of HrIL-1 beta induced a delayed inflammation peaking at 10 h instead at 6 h.

Direct high-performance liquid chromatographic resolution of the enantiomers of tiaprofenic acid using immobilized human serum albumin.

Resolution of racemic tiaprofenic acid (TA) has been performed using immobilized human serum albumin as the stationary phase. The eluent was phosphate buffer-acetonitrile-n-octanoic acid (90:10:0.015, v/v). Detection was achieved at 305 nm. The pharmacokinetics of the enantiomers were studied following oral administration into humans and after subcutaneous injection in rats. Plasma concentrations of (+)-TA were much greater than those of (-)-TA. For the rat, the pharmacokinetic parameters between (-)-TA and (+)-TA were all statistically different (p < 0.005).

Pro- and anti-inflammatory properties of human recombinant IL-1 beta during experimental arthritis in rats: 2. Period-dependent effect.

The systemic effects of human recombinant Interleukin-1 beta (HrIL-1 beta) on hindpaw edema were determined in arthritis induced by human native type II collagen (CII) with muramyl dipeptide (MDP) both injected on day 0. Daily treatment with HrIL-1 beta (0.2 microgram sc) pretreatment, from D-1 (the day before MDP and CII were injected) to D3 significantly delayed the secondary inflammation in the uninjected left hindpaw, whereas the same treatment from D6 to D10 at the end of the "primary" inflammation, enhanced the volume of the left hindpaw. Treatment from D13 to D17 did not affect the "secondary" edema in the left hindpaw. Thus, HrIL 1 beta administration produces pro- or anti-inflammatory effects on a developing polyarthritis depending on when treatment is started and is most effective as an anti-inflammatory molecule when started at the peak of the the inflammatory reaction, as previously described. In view of these early findings, we have compared the effect of adding HrIL-1 beta along with MDP in the sensitization procedure on the time-course of CII-induced arthritis. No adjuvant effect of HrIL-1 beta was observed. On the contrary, HrIL-1 beta significantly decreased the signs of inflammation in the injected hindpaw during the secondary inflammation. In addition, the immune response to type II collagen was less in the group receiving HrIL-1 beta, maybe because of nonspecific increase of antigen clearance. On the other hand, the MDP sensitization procedure enhanced the incidence of CII arthritis and significantly worsened the clinical parameters in both primary and secondary inflammations.

Pro- and anti-inflammatory properties of human recombinant IL-1 beta during experimental arthritis in rats: 1. Dependence on dose and severity threshold.

The effects of human recombinant interleukin-1 beta (HrIL-1 beta) were investigated in arthritic rats sensitized with type II collagen (CII) and muramyl dipeptide (MDP). When administered subcutaneously (sc) daily during established arthritis, low (0.02 micrograms) and medium (0.2 micrograms) HrIL-1 beta doses exerted paradoxical beneficial properties on paws with moderate and severe inflammation, respectively. In contrast, the highest dose (2 micrograms) had a pejorative effect on developing arthritis. In addition, HrIL-1 beta attenuated paw volume and deterioration of the joints as assessed radiologically. Hence, paw inflammation response to IL-1 exposure depended on the dosage and the severity of previous arthritis prior to the IL-1 challenge. Some of these paradoxical activities may be due to the capacity of IL-1 to induce its own inhibitors or feedback loops thus counterbalancing its phlogistic properties.

Assay of circulating hyaluronic acid in the rat: study of diurnal variation and effect of anesthesia.

Serum hyaluronic acid (HA) may provide a good marker for the severity of joint disease in the rat since a positive correlation was observed in experimental models of arthritis. However, little is known about its physiological variation in rats. In the present work, we do not find any circadian rhythm of HA in healthy Sprague-Dawley rats in contrast to that observed in humans, whose serum levels vary during daytime. Furthermore, the influence of blood sampling conditions on HA concentrations was evaluated in conscious animals and by using different anesthetics. The greater reproducibility for the assay of HA is observed with the intracardiac puncture under ether inhalation. Blood sample collection in the absence of anesthesia leads to a significant increase in serum levels of HA, which could be attributed partly to enhanced joint movements generated by psychological stress.

Auto-immune spondylodiscitis associated with collagen induced arthritis in rats: high field MRI findings.

The spinal involvement of the tail was studied in Wistar Furth rats immunized with bovine native type II collagen. Focal caudal autoimmune spondylodiscitis occurred 5 weeks after sensitization, as assessed histopathologically. High field Magnetic Resonance Imaging (MRI) was useful in depicting these caudal abnormalities that were related to juxta-diskal enthesitis. The occurrence of such inflammatory enthesopathies could serve as an experimental approach for physiopathological and therapeutical studies of spondylarthropathies.

Influence of muramyl dipeptide on established experimental arthritis in rats.

The effects of MDP, a potent inducer of cytokines, were studied in four batches of Wistar Furth rats with established experimental arthritis. Arthritic rats were given a daily sc injection of 10, 100, 200 or 400 micrograms MDP respectively. Muramyl dipeptide increased the severity of clinical events in a dose-dependent manner, with the exception of the 10 micrograms dose which was ineffective. The levels of anti-collagen antibodies were not however significantly enhanced by MDP. Radiological lesions and histological changes were maximal at high dosage regimens. Paradoxically, the acute phase reactive alpha 1 glycoprotein was little affected by MDP treatment.

Lack of adjuvanticity of human recombinant interleukin-1 beta in collagen induced arthritis in rats.

We investigated the influence of human recombinant interleukin-1 beta (hrIL-1 beta) on the time-course of collagen induced arthritis (CIA) when injected concomitantly with the arthritogenic emulsion. Three sensitizing procedures were compared. The control group received type II collagen only. The other groups differed by the adjunction of demonstrated (MDP) or potential (IL-1 beta) adjuvant. No adjuvant effect of IL-1 was observed as judged on clinical or radiological scores. On the contrary, MDP significantly worsened the lesions of the injected right hindpaw, and increased the incidence of CIA. Surprisingly, humoral response to type II collagen was decreased in the group receiving IL-1 beta. This might be explained by a non specific increase of antigen clearance.