Philippe Mangin

Quantification of expression of netrins, slits and their receptors in human prostate tumors

Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real‐time quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over‐expressed either Slit genes or their receptors, Robo.

Combination of Polymorphisms From Genes Related to Estrogen Metabolism and Risk of Prostate Cancers: The Hidden Face of Estrogens

PURPOSE The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated. PATIENTS AND METHODS The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers. RESULTS The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients. CONCLUSION This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways.

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

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.

PCAP is the major known prostate cancer predisposing locus in families from south and west Europe

To date four prostate cancer predisposing loci have been mapped: HPC1 (Hereditary Prostate Cancer 1) on 1q24-25, PCaP (Predisposing for Cancer Prostate) on 1q42.2-43, CAPB (Cancer Prostate and Brain) on 1p36, and HPCX on Xq27-28. We examined evidence for linkage to those loci in 64 families from south and west Europe. Genotyping of three (six for PCaP) markers encompassing the candidate regions were performed on 221 individuals including 159 affected patients. The resulting data were analysed using both parametric and non parametric linkage methods. No significant evidence of linkage to HPC1, CAPB, or HPCX was found either in the whole population or when pedigrees were stratified according to criteria specific to each locus. By contrast, results in favour of linkage to PCaP locus were observed with maximum multipoint NPL and HLOD scores of 2.8 (P = 0.0026) and 2.65 respectively. Homogeneity analysis performed with multipoint LOD scores gave an estimated proportion of families with linkage to this locus up to 50%. Particularly, families with an earlier age at diagnosis (⩽65-years-old) contributed significantly to the evidence of linkage with a maximum multipoint NPL score of 2.03 (P = 0.024). Those results suggest that PCaP is the most frequent known locus predisposing to hereditary prostate cancer cases from families from south and west Europe.

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 probands 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. Int. J. Cancer 86:883–887, 2000.

DIAGNOSIS OF FEMALE BLADDER OUTLET OBSTRUCTION AND RELEVANCE OF THE PARAMETER AREA UNDER THE CURVE OF DETRUSOR PRESSURE DURING VOIDING: PRELIMINARY RESULTS

PURPOSE The diagnosis of bladder outlet obstruction in women by pressure flow study may be difficult because there are several definitions of bladder outlet obstruction, several parameters and no standard cutoffs. We evaluated the ability of pressure flow studies to separate women into unobstructed, equivocal and obstructed groups. MATERIALS AND METHODS In a prospective study 85 women with lower urinary tract symptoms underwent clinical evaluation, including physical examination, voiding cystourethrography, endoscopy, flow rate and post-void residual volume measurement. A pressure flow study was performed 15 days later. The pressure flow study parameters were maximum flow, post-void residual volume, detrusor pressure at maximum flow, vesical pressure at maximum flow, area under the curve of detrusor pressure during voiding and area under the curve of detrusor pressure during voiding adjusted for voided volume. After considering the clinical evaluation 2 urologists classified the patients into 3 groups, namely unobstructed, equivocal and obstructed, as the traditional classification. Linear discriminant analysis was then performed using the traditional classification and pressure flow study data. RESULTS Mean patient age was 55 years (range 18 to 83). According to the traditional classification there were 36 unobstructed, 28 equivocal and 21 obstructed cases. Significant differences were noted in all pressure flow study parameters (analysis of variance p <0.05). Linear discriminant analysis showed that area under the curve of detrusor pressure during voiding adjusted for voided volume was the most statistically discriminating parameter. Of the cases 86%, 36% and 57% were identically categorized by the traditional and area under the curve of detrusor pressure during voiding adjusted for voided volume parameter classifications in the unobstructed, equivocal and obstructed groups, respectively. The other pressure flow study parameters showed less satisfactory results. CONCLUSIONS Area under the curve of detrusor pressure during voiding adjusted for voided volume appears to be the most discriminating urodynamic parameter of female bladder outlet obstruction. Other studies are needed to test the reliability and validity of this new parameter.

Urinary morbidity after 125I brachytherapy of the prostate

To assess urinary morbidity within the first 6 months after transperineal prostate brachytherapy (TPBT) with 125I for localized prostate adenocarcinoma.

Three-dimensional CT-scan reconstruction of renal calculi. A new tool for mapping-out staghorn calculi and follow-up of radiolucent stones.

OBJECTIVES The development of CT scanners (CT scan) with continuous rapid spiral acquisition now allows three-dimensional reconstructions of mobile organs such as kidneys. The aim of this study was to appreciate the merits of this new technique in the field of renal lithiasis. METHOD This non-invasive technique was applied in 27 renal calculi (23 staghorn and 4 radiolucent stones). The acquisition does not require any injection of contrast material. Reconstruction was carried out by three-dimensional (3D) shaded surface display. RESULTS 3D reconstruction of calculi permits a precise study of the shape of the stone, and of the number, size and direction of its branches. Therefore, it allows for better planning of the PCNL (number of ports, per-operative pelvi-caliceal exploration ...). Large radiolucent calculi are clearly defined with 3DS, facilitating the follow-up under medical treatment. CONCLUSION 3D CT scan reconstruction is a noninvasive, cost-effective method which offers high quality 3D images of renal calculi. These results should spur the more widespread use of this technique.

Association between estrogen and androgen receptor genes and prostate cancer risk

OBJECTIVE Prostate cancer (PC) is one of the principal causes of death among men. Steroid hormones are involved in normal prostate growth and carcinogenesis. The purpose of our study was to investigate the effects on PC risk of polymorphisms from three steroid hormone receptor genes: the androgen (AR), and the alpha (ESR1) and beta (ESR2) estrogen receptors. DESIGN AND METHODS The study was performed on a Caucasian population of 1045 PC patients and 814 controls. Using a logistic regression model, the different alleles and genotypes from those polymorphisms were analyzed according to case/control status, the tumor aggressiveness, and the age at onset. RESULTS A significant association between PC risk and the pooled 4/5, 5/6, and 6/6 genotypes of the GGGA repeat located in the first intron of ESR1 (odds ratio (OR)=3.00, 95% CI=1.32-6.82, P=0.008) was observed. When we stratified the cases, this association was confined to patients with a Gleason score of 2-4 (OR=8.34, 95% CI=2.91-23.91, P<0.0001) or late onset PC (OR=2.91, 95% CI=1.22-6.93, P=0.016). An association between a short AR CAG repeat (less than 17 repeats) was also observed among patients with late onset PC (OR=2.34, 95% CI=1.15-4.76, P=0.019). CONCLUSIONS These findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.

Association study of polymorphisms in the human estrogen receptor alpha gene and prostate cancer risk

OBJECTIVES Prostate cancer is a very common hormone-related malignancy in Western countries. It is initially dependent on androgen stimulation but in vitro growth of prostate cancer cells are also dependent on estrogen. Our goal was to elucidate if some polymorphisms of estrogen receptor alpha gene might be associated with the risk of prostate cancer. METHODS Using DHPLC techniques, each coding exon of the estrogen receptor alpha gene was screened for new polymorphisms in germline DNA from 96 healthy controls and 96 sporadic prostate cancer cases. Identified polymorphisms were then genotyped and their distribution compared between the two populations. RESULTS Thirteen polymorphisms were identified. A difference was found in the distribution of one newly identified polymorphism, namely a GGGA repeat located in the first intron of the gene. The common wild type genotype consisted of two alleles with five GGGA repetitions (5/5 genotype). Indeed this 5/5 genotype was found in 294/296 controls (99.3%) and 285/294 patients (96.9%; OR, 4.6; 95% CI, 0.99-21.67). Among the nine patients with a different genotype, one was 4/5, seven were 5/6 and one was 6/6. CONCLUSION These results suggest that variants of the GGGA polymorphism from the estrogen receptor alpha gene may be associated with an increased risk of developing prostate cancer.