Georges Fournier

Publications (24)119.02 Total impact

• Article: VEGFR1 and NRP1 Endothelial Expressions Predict Distant Relapse after Radical Prostatectomy in Clinically Localized Prostate Cancer.

  Matthieu Talagas, Arnaud Uguen, Ronan Garlantezec, Georges Fournier, Laurent Doucet, Eric Gobin, Pascale Marcorelles, Alain Volant, Marc DE Braekeleer
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  ABSTRACT: Prostate cancer can usually be treated at a clinically localized stage by radical prostatectomy. Unfortunately, within 10 years following surgery, 30% of patients experience local or distant relapse. Few data exist on the association of markers of angiogenesis and distant relapse after radical prostatectomy. By immunohistochemistry in tissue microarray, we compared the expression pattern of hypoxia inducible factor 1, alpha subunit (HIF1α) and vascular endothelial growth factor (VEGF) and its receptors in 45 patients with distant relapse and 68 patients without relapse after radical prostatectomy. Expressions of HIF1α and VEGF were assessed in prostate tumor cells and those of VEGFR1, VEGFR2 and neuropilin 1 in tumor and endothelial cells. The five molecules studied were expressed by all tumors, with the exception of neuropilin 1 in endothelial cells for one tumor. Strong endothelial expression of VEGFR1 appeared to be an independent predictor of distant relapse. A moderate to strong endothelial expression of neuropilin 1 was in turn an independent predictor of absence of distant relapse. No significant difference was found for HIF1α, VEGF, VEGFR1, VEGFR2 and neuropilin 1 expression in tumor cells, nor for VEGFR2 in endothelial cells, between the two groups. To our knowledge, this is the first study to evaluate the prognostic value of VEGFR1, VEGFR2 and neuropilin 1 in endothelial cells in prostate cancer after radical prostatectomy. The evaluation by immunohistochemistry of endothelial expression of neuropilin 1 and VEGFR1 could be an additional tool in the assessment of tumor aggressiveness of clinically localized prostate cancer to better identify patients at high risk of distant relapse.
  Anticancer research 05/2013; 33(5):2065-75. · 1.73 Impact Factor
• Article: BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy.

  Gaelle Fromont, François Rozet, Xavier Cathelineau, Adil Ouzzane, Laurent Doucet, Georges Fournier, Olivier Cussenot
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  ABSTRACT: Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case-control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools. Among 1,200 patients treated by radical prostatectomy with negative margins with at least 4 years follow-up, 121 prostate cancers with biochemical relapse were matched after pathological reassessment with 121 cancers with identical clinicopathological features but without relapse. Immunohistochemistry was performed on tissue microarrays, using antibodies directed against molecules involved in androgen and estrogen signaling, including hormone receptors, enzymes (such as the five alpha reductases 1,2 and 3, aromatase, alpha-keto reductase 1C3 and squalene epoxidase), the breast cancer antiestrogen resistance 1 (BCAR1), and the proliferation marker Ki67. The median follow-up for patients without recurrence was 7 years. Both cell proliferation and BCAR1 expression were significantly associated with biochemical relapse, in univariate and multivariate analysis. In subgroup analysis, the sole predictive marker in patients with well-differentiated prostate cancer was BCAR1 (P = 0.004), whereas only proliferation (P = 0.001) was significantly associated with relapse in less-differentiated prostate cancer patients. BCAR1 is an independent predictor of recurrence after radical prostatectomy for "low risk" prostate cancer. The use of this biomarker may enable more individualized treatment approaches.
  The Prostate 01/2012; 72(12):1359-65. · 3.48 Impact Factor
• Article: Fascia surrounding the prostate: clinical and anatomical basis of the nerve-sparing radical prostatectomy.

  Jean-Nicolas Cornu, Véronique Phé, Georges Fournier, Vincent Delmas, Philippe Sèbe
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  ABSTRACT: Nerve-sparing radical prostatectomy (NSRP) is based on anatomical considerations that are still controversial. The aim of this study is to define and describe the anatomy of the fascias surrounding the prostate in a histoembryologic model and during open and laparoscopic approaches to assess their importance in surgical practice. An anatomical dissection of three fresh cadavers was conducted to reproduce an open approach. Complementary data under laparoscopic conditions were obtained from images captured from the video feed during a laparoscopic NSRP performed via a transperitoneal approach. A histological study of one fresh 25-week human male fetus, obtained following miscarriage, was also conducted to document the embryologic development of the identified fascias. Three fascias surrounding the prostate can clearly be individualized both in histologic and clinical conditions. The endopelvic fascia (EF), the prostatic fascia (PF) and the Denonvilliers' fascia (DF) recover the prostate gland and structure the periprostatic environment. Neurovascular bundles are situated in a triangle formed by PF, EF and DF. Interfascial dissection (between EF and PF) allows nerve-sparing surgery. When performing radical prostatectomy, it is mandatory to locate EF, PF and DF precisely to respect the neurovascular bundles. Nevertheless, cancer extension and anatomic variations can lead to more extensive procedures.
  Anatomia Clinica 08/2010; 32(7):663-7. · 0.93 Impact Factor
• Article: Effect of genetic variability within 8q24 on aggressiveness patterns at diagnosis and familial status of prostate cancer.

  Olivier Cussenot, Abdel-Rahmène Azzouzi, Gladys Bantsimba-Malanda, Cecile Gaffory, Philippe Mangin, Luc Cormier, Georges Fournier, Antoine Valeri, Lionel Jouffe, Morgan Roupret, Gaelle Fromont, Mathilde Sibony, Eva Comperat, Géraldine Cancel-Tassin
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  ABSTRACT: Recently, two independent loci located at 8q24 that contribute to prostate cancer risk in men of European origin were identified. Using Bayesian probability network and logistic regression model, we searched for associations between 34 single-nucleotide polymorphisms (SNP) located at 8q24 and the aggressiveness patterns of prostate adenocarcinoma or familial history of cancers in 823 White Caucasian French men. Probability network according to the Markov chain algorithm separated the SNPs into two main groups: The first one was linked to the locus marked by rs6983267 and the second one was linked to the locus marked by rs1447295. When the patients were stratified according to tumor stage and prostate-specific antigen value, the association between the variant genotypes from six SNPs located in the second network and prostate cancer risk was strongest or confined to the patients from the more aggressive classes. However, the association between prostate cancer risk and the CC genotype of rs7841264, which marked the recombination hotspot at 8q24, was confined to patients with the highest Gleason score (odds ratio, 2.15; 95% confidence interval, 1.27-3.64; P=0.004). Interestingly, the G allele of rs6983267 was associated with familial prostate cancer risk. Our data further support that variability at 8q24 is associated with a high risk of aggressive prostate cancer at diagnosis and is linked with familial history of prostate cancer. These results corroborate that 8q24 SNPs must be evaluated in terms of prostate cancer aggressiveness markers to optimize early diagnosis procedures and management of the disease.
  Clinical Cancer Research 10/2008; 14(17):5635-9. · 7.74 Impact Factor
• Article: Association between estrogen and androgen receptor genes and prostate cancer risk.

  Nathalie Nicolaiew, Geraldine Cancel-Tassin, Abdel Rahmene Azzouzi, Beatrice Le Grand, Philippe Mangin, Luc Cormier, Georges Fournier, Jean-Pierre Giordanella, Michel Pouchard, Jean-Louis Escary, Antoine Valeri, Olivier Cussenot
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  ABSTRACT: 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. 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. 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). These findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.
  European Journal of Endocrinology 10/2008; 160(1):101-6. · 3.42 Impact Factor
• Article: Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors.

  Olivier Cussenot, Abdel-Rahmène Azzouzi, Nathalie Nicolaiew, Philippe Mangin, Luc Cormier, Georges Fournier, Antoine Valeri, Géraldine Cancel-Tassin
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  ABSTRACT: The 5-alpha-reductase type 2 (5A2) enzyme catalyses the irreversible conversion of testosterone to dihydrotestosterone, the most active androgen in the prostate. This key enzyme in prostate gland physiopathology has recently been targeted by using inhibitors for chemoprevention of prostate cancer. However, some controversies have arisen by the observation of greater than expected high-grade tumours in men diagnosed with prostate cancer in the finasteride chemoprevention trial. To help understand the impact of prolonged exposure to low 5A2 activity on prostate cancer risk, we analysed the rather common genetic V89L polymorphism, which has previously been well characterised functionally for determining low enzymatic activities. The study was performed on 1605 white Caucasian French men categorised in 803 patients with prostate adenocarcinoma and 802 matched healthy male controls. The different alleles and genotypes were analysed according to case-control status and the aggressiveness pattern of the tumours. The V89L amino acid substitution leading to the homozygous genotype LL increased the risk of clinically significant disease (odds ratio [OR]=1.89, 95% confidence interval (%95 CI), 1.07-2.74; p=0.0017) and was also associated with the most aggressive patterns of the disease (OR=2.56, 95%CI, 1.41-4.63; p=0.002). Our data confirm in a large and homogeneous Caucasian French population that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer. These results corroborate that long-term exposure to 5A2 inhibitors (chemoprevention) must be evaluated in terms of risk of prostate cancer adverse effects.
  European Urology 11/2007; 52(4):1082-7. · 8.49 Impact Factor
• Article: Combination of polymorphisms from genes related to estrogen metabolism and risk of prostate cancers: the hidden face of estrogens.

  Olivier Cussenot, Abdel Rhamene Azzouzi, Nathalie Nicolaiew, Gaelle Fromont, Philippe Mangin, Luc Cormier, Georges Fournier, Antoine Valeri, Stephane Larre, Frederic Thibault, Jean-Pierre Giordanella, Michel Pouchard, Yan Zheng, Freddie C Hamdy, Angela Cox, Geraldine Cancel-Tassin
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  ABSTRACT: 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. 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. 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. 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.
  Journal of Clinical Oncology 08/2007; 25(24):3596-602. · 18.37 Impact Factor
• Source

  Available from: eu-acme.org

  Article: Renal cell carcinoma in adults 40 years old or less: young age is an independent prognostic factor for cancer-specific survival.

  Xavier Taccoen, Antoine Valeri, Jean-Luc Descotes, Vincent Morin, Eric Stindel, Laurent Doucet, Vincent Joulin, Frederic Bocqueraz, Christian Coulange, Jean-Jacques Rambeaud, Georges Fournier, Arnaud Mejean
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  ABSTRACT: Renal cell carcinoma (RCC) is uncommon in young adults. Based on the few studies published to date, it is difficult to determine whether this tumour has a particular progression pattern. This retrospective, multicentre study analysed RCC in young patients, defined as </=40 yr old, compared to RCC in older patients. Between 1988 and 2000, 1233 patients, 93 under 40 yr old and 1140 older (mean ages, 34.2 and 61.9 years, respectively) underwent surgery for RCC in four teaching hospitals. Clinical and biologic parameters at diagnosis were compared and subjected to univariate and multivariate analyses to study survival. Mean follow-up was 4.5 yr for young and 4.1 yr for older patients. When comparing younger to older patients, respectively, they had a lower male-to-female ratio (1.2 vs. 2.5), lower stage (84.9% vs. 67.4% pT1-pT2N0M0; p=0.001), and fewer clear-cell carcinomas (73.1% vs. 82%), but more papillary carcinomas (20.4% vs. 11.4%; p=0.01) and better 5-yr cancer-specific survival rates (90.8% vs. 78.3%; p=0.005). Independent prognostic factors for survival, in the order of decreasing impact, were tumor stage (p<0.0001), Fuhrman nuclear grade (p<0.0001), and age </=40 yr at diagnosis (risk ratio 0.4, p<0.047). Young patients tended to have a better 5-yr progression-free survival (80.5% vs. 70.7%; p=0.05). RCC in young adults was more often localised at diagnosis and had a better prognosis than the disease in older subjects. Age under 40 yr old was an independent prognostic factor for survival.
  European Urology 04/2007; 51(4):980-7. · 8.49 Impact Factor
• Article: Differential expression of 37 selected genes in hormone-refractory prostate cancer using quantitative taqman real-time RT-PCR.

  Gaëlle Fromont, Laurent Chene, Michel Vidaud, Guy Vallancien, Philippe Mangin, Georges Fournier, Pierre Validire, Alain Latil, Olivier Cussenot
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  ABSTRACT: Progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. The development of more effective treatments depends on our understanding of the molecular events associated with the hormone-refractory stage. We quantified, among 90 screened genes, the expression of 37 target genes, using real-time quantitative RT-PCR. Gene expression was studied in 13 samples of HPRC compared to 33 clinically localised cancers and normal prostate tissue. We identify 19 genes with significant differential expression in HRPC compared to localised prostate cancer. Genes with decreased expression included receptors for growth factors, MMR genes and the serine protease hepsin. Analysis of increased gene expression confirmed the importance of AR upregulation and highlighted genes not previously linked to HRPC, including enzymes involved in steroid synthesis and the antiapoptotic factor survivin. Progression of prostate cancer to the hormone-refractory state is associated with differential gene expression, which may prove useful for both understanding disease progression and the development of new therapeutic approaches.
  International Journal of Cancer 04/2005; 114(2):174-81. · 5.44 Impact Factor
• Article: [Idiopathic acute partial renal infarction].

  Vincent Joulin, Federico Sallusto, Charles Deruelle, Xavier Taccoen, Antoine Valeri, Georges Fournier
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  ABSTRACT: Renal infarction is a rare disease which must be considered in any case of low back pain. The most frequent causes are related to emboligenic heart disease, renal artery fibrodysplasia or trauma. The authors report the second published case of idiopathic renal infarction. The diagnosis is usually suggested by contrast-enhanced abdominal CT scan, but is confirmed and refined by selective renal arteriography or CT angiography. Treatment may be medical or surgical depending on the severity of the lesions and the patient's general state. The therapeutic indications are discussed in the light of a review of the literature.
  Progrès en Urologie 03/2005; 15(1):75-7. · 0.58 Impact Factor
• Article: Testicular adrenal rest tumours in salt wasting congenital adrenal hyperplasia (in vivo and in vitro studies).

  Jean Pierre Bercovici, Jean Fiet, Laurence Gibault, Alain Volant, Jean Hervé Abalain, Hervé Henri Floch, Emmanuel Sonnet, Georges Fournier
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  ABSTRACT: We describe the case of a 20-year-old patient with salt-wasting congenital adrenal hyperplasia (CAH) related to 21-hydroxylase deficiency. Bilateral craggy testicular tumours were found, requiring histological evaluation. Prior to the surgical procedure, the patient was treated with dexamethasone (he presented cortisol deficiency) and was stimulated with ACTH. High levels of 11beta-OH steroids measured in the gonadal vein, compared with peripheral blood samples suggested the presence of adrenal rests. Incubation of the tumours (which could not be differentiated histologically, from Leydig tissue), with radioactive steroid precursors was carried out. The results revealed the testicular tumours were of adrenal tissue origin, associated with 21-hydroxylase deficiency. The patient's non-compliance to glucocorticoid treatment was the main cause of his hypogonadotropic hypogonadism.
  The Journal of Steroid Biochemistry and Molecular Biology 02/2005; 93(1):67-72. · 3.05 Impact Factor
• Article: Molecular profiling of benign prostatic hyperplasia using a large scale real-time reverse transcriptase-polymerase chain reaction approach.

  Gaëlle Fromont, Laurent Chene, Alain Latil, Ivan Bieche, Michel Vidaud, Guy Vallancien, Philippe Mangin, Georges Fournier, Pierre Validire, Olivier Cussenot
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  ABSTRACT: Benign prostatic hyperplasia (BPH) is characterized by a hyperplastic growth of epithelial and stromal cells in the prostate. Despite the high prevalence of the disease little is known regarding the molecular etiology of BPH. Therefore, a comparison of gene expression patterns between normal prostate, BPH and prostate cancer could provide insights into the pathogenic mechanisms of the disease and identify candidate genes that could be targeted for therapeutic use. Prostate tissue specimen were obtained from 30 patients undergoing adenomectomy for BPH. Adenoma weight was less than 60 gm in 15 patients and more than 60 gm in the remainder. Normal prostate tissue was obtained from 15 patients undergoing radical prostatectomy for cancer from areas selected for absent tumor and BPH. Two pools of organ confined prostate cancer were also analyzed. We quantified in the 5 pools of tissues the expression of 327 genes using real-time quantitative reverse transcriptase-polymerase chain reaction. A total of 23 genes showed increased expression in BPH with a fold change of at least 2.5 between normal prostate and the 2 BPH groups, of which most were normal or down-regulated in prostate cancer. Seven genes showed decreased expression in BPH with a fold change of at least 3.5 between normal prostate and BPH. Most of them were also normal or down-regulated in prostate cancer. We identified a set of genes up-regulated in BPH compared to normal prostate tissue and often prostate cancer, including genes previously implicated in BPH and others not previously linked to this disease to our knowledge. Further investigations are now warranted to determine the clinical relevance and therapeutic potential of these genes.
  The Journal of Urology 11/2004; 172(4 Pt 1):1382-5. · 3.75 Impact Factor
• Article: Expression in bladder transitional cell carcinoma by real-time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1-2: identification of 5 candidates tumor suppressor genes.

  Najla Amira, Géraldine Cancel-Tassin, Stéphane Bernardini, Béatrix Cochand-Priollet, Hugues Bittard, Philippe Mangin, Georges Fournier, Alain Latil, Olivier Cussenot
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  ABSTRACT: Frequent deletions on 9q34.1-2 were reported in bladder transitional cell carcinoma. High deletion mapping studies delimited a critical interval between markers D9S61 and D9S66, which is highly susceptible to contain a tumor suppressor gene. Expression level of the 65 genes localized in this region was analyzed by real-time quantitative RT-PCR, comparing tumor to normal urothelium. Five genes exhibited a significantly reduced expression level: C9orf9, KIAA0625, ABL1, LAMC3 and KIAA1857-netrin-G2, which exhibited the most significant downregulation (p=0.0007). KIAA1857-netrin-G2 belongs to the netrins and might then be a tumor suppressor gene in bladder cancer, as netrin1 receptor DCC has been implicated in tumorigenesis.
  International Journal of Cancer 10/2004; 111(4):539-42. · 5.44 Impact Factor
• Article: Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer.

  Xavier Roumier, Rahmene Azzouzi, Antoine Valéri, Francis Guillemin, Georges Fournier, Olivier Cussenot, Philippe Mangin, Luc Cormier
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  ABSTRACT: To assess the adherence to an annual PSA screening program conducted over 3 years in first-degree relatives of a sample of men with prostate cancer, and to identify characteristics of men who failed to undergo the full screening process. Out of 747 candidates that were eligible for the screening program (asymptomatic brothers and sons aged between 40 and 70 years of men diagnosed with prostate cancer) 640 were contacted. The screening program entailed annual serum PSA testing over a 3-year period, during which every candidates attendance was recorded. At the outset, each candidate was requested to complete a questionnaire regarding their socio-professional characteristics, their level of anxiety and their attitude towards genetic susceptibility. 442 (69%) candidates agreed to enter the study and 420 filled out the questionnaire. During the 3-year period, 50 candidates (12%) who had accepted the first year screening refused to undergo subsequent PSA tests. These men were younger ( p=0.015), more anxious (p=0.037 ) and to have more than one affected first-degree relative ( p=0.028 ). The crucial and challenging step in the adherence to a screening program was the initial recruitment. Once recruited, adherence rate after 3 years was very high (88%). Identifying factors that help predict men who might leave the screening process may provide us means of improving their compliance in the future.
  European Urology 04/2004; 45(3):280-5; author reply 285-6. · 8.49 Impact Factor
• Article: Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion.

  Alain Latil, Laurent Chêne, Philippe Mangin, Georges Fournier, Philippe Berthon, Olivier Cussenot
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  ABSTRACT: Loss of heterozygosity (LOH) on chromosome arm 13q14 is one of the most consistent genetic alterations in sporadic prostate cancer. This alteration may be involved in prostate oncogenesis through inactivation of one or more tumor suppressor genes (TSGs). Candidate gene expression is an approach to focus the search for TSGs in this region. We tested 41 human sporadic prostate tumors for 13q14 LOH by using seven polymorphic markers overlapping the critical region and used a real-time quantitative RT-PCR assay to study the same tumors for expression of the 31 genes located in this genomic region (localized by the Human Genome Project Working Draft). Allelic loss on at least one locus was found in 18 (41%) of the 41 tumor DNAs. Only four genes (ITM2B, CHC1L, KIAA0970, and LOC51131), located in the region most frequently deleted in prostate carcinoma, showed a significant difference in expression between normal and neoplastic prostate tissues. Given their location in the LOH hotspot, as indicated by our genomic analysis, ITM2B, CHC1L, KIAA0970, and LOC51131 are candidate tumor suppressor genes in this region. ITM2B that showed a significant association (P < 0.005) between expression and LOH at the corresponding locus could, furthermore, be the main target of the observed LOH at 13q in prostate tumors.
  The Prostate 09/2003; 57(1):39-50. · 3.48 Impact Factor
• Article: Familial prostate cancer cases before and after radical prostatectomy do not show any aggressiveness compared with sporadic cases.

  Abdel-Rahmene Azzouzi, Antoine Valeri, Luc Cormier, Georges Fournier, Philippe Mangin, Olivier Cussenot
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  ABSTRACT: To compare the clinical and biologic features at diagnosis between sporadic and familial clinically localized prostate cancer (CaP), and to compare the prognosis of familial with that of sporadic cases after radical prostatectomy in southwestern Europe. Eighty-five sporadic (one case of CaP) and 37 familial (two or more CaP cases in the family) patients with clinically localized CaP undergoing radical prostatectomy were compared regarding preoperative (mean age, clinical status, mean prostate-specific antigen level, and mean Gleason score at diagnosis) and postoperative (pT, pN, and pathologic Gleason score) parameters using the Student t test, Fisher's exact test, and the chi-square test. The biochemical relapse-free survival for each group was compared using the Kaplan-Meier method and the log-rank test. The mean follow-up was about 51.8 months (range 1 to 156) in the sporadic group and 35 months (range 1 to 96) in the familial group. No specific preoperative and postoperative clinical or biologic feature was associated with familial CaP. Biochemical relapse occurred in 40.5% (15 of 37) of cases when the proband had a positive family history of CaP versus 32.9% (28 of 85) in the sporadic cases (P = 0.42). Biochemical relapse-free survival curves did not display any difference (P = 0.46) between familial and sporadic CaP. In this population, the outcome after radical prostatectomy is similar in those with and without a family history. Thus, the natural history of CaP seems to follow the same path whether the triggering point is inherited or acquired for this subset of patients during this period.
  Urology 07/2003; 61(6):1193-7. · 2.43 Impact Factor
• Article: Quantification of expression of netrins, slits and their receptors in human prostate tumors.

  Alain Latil, Laurent Chêne, Béatrix Cochant-Priollet, Philippe Mangin, Georges Fournier, Philippe Berthon, Olivier Cussenot
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  ABSTRACT: 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.
  International Journal of Cancer 02/2003; 103(3):306-15. · 5.44 Impact Factor
• Source

  Available from: Philippe Mangin

  Article: Impact of constitutional genetic variation in androgen/oestrogen-regulating genes on age-related changes in human prostate.

  Abdel-Rahmene Azzouzi, Beatrix Cochand-Priollet, Philippe Mangin, Georges Fournier, Philippe Berthon, Alain Latil, Olivier Cussenot
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  ABSTRACT: Benign prostatic hyperplasia (BPH) is the most common benign tumour in ageing men. While the etiopathology remains unsolved, a disruption in the endocrine/autocrine-paracrine prostatic homeostasis, involving steroid hormones, contributes to the pathogenesis of BPH. DNA polymorphisms in genes involved in hormone synthesis, signalling and metabolism may, therefore, be responsible for these changes. We have evaluated the correlation between specific genotypes in androgen- and oestrogen-regulating genes (AR, SRD5A2, CYP17 and CYP19), and age-related prostatic changes. We have tested genetic susceptibility to morphological and pathological criteria in 195 French Caucasians, using allelic variants for candidate genes involved in androgen/oestrogen prostatic activity: androgen receptor (CAG repeats), 5alpha-reductase type 2 (TA repeats, V89L and A49T mutations), A2 variant of the 17alpha-hydroxylase (CYP17) and the simple tandem repeat polymorphism (STRP) aromatase (CYP19) polymorphisms. The A2 variant of 17alpha-hydroxylase (CYP17) and allele 191 of STRP aromatase (CYP19) showed an opposite effect on age-related prostate hyperplasia: CYP17 being associated with increased risk of prostate enlargement and CYP19 with reduced risk. The 5alpha-reductase type II variants studied did not show links with prostate hyperplasia. The androgen receptor gene CAG repeat length showed a low correlation with the increase of prostate weight, suggesting some effect on age-related prostate growth. These results suggested that common variants of the CYP17 gene are associated with prostate enlargement and therefore may increase the risk of development of BPH in this population, while infrequent variants of the aromatase gene (CYP19) could be of a protective nature.
  European Journal of Endocrinology 11/2002; 147(4):479-84. · 3.42 Impact Factor
• Article: Down-regulation of (IIIb) and (IIIc) isoforms of fibroblast growth factor receptor 2 (FGFR2) is associated with malignant progression in human prostate.

  Benyoussef Naimi, Alain Latil, Georges Fournier, Philippe Mangin, Olivier Cussenot, Philippe Berthon
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  ABSTRACT: Fibroblast growth factors (FGFs) and their receptors (FGFRs) have a critical function in the cellular stroma/epithelium interaction for the development and homeostasis of human prostate. Imbalance in expression of these factors is associated with malignancy in several cancers. To quantify the expression of fibroblast growth factor receptor isoforms FGFR2(IIIb), FGFR2(IIIc), FGFR1(IIIc), and fibroblast growth factors FGF2 and FGF7 in normal and tumoral human prostate tissues, and human prostatic epithelial cell lines, we used quantitative real-time polymerase chain reaction. The expression of FGFR2(IIIb) mRNA is down-regulated in 60% of the tumors studied (P < 0.0001). Furthermore, FGFR2(IIIb) is significantly reduced in androgen-independent tumors (AI) compared with androgen-responsive tumors (AD) (P = 0.02). A significant reduction in FGFR2(IIIc) expression is also observed in 80% of tumors (P = 0.001). However, unlike FGFR2(IIIb), the down-regulation of FGFR2(IIIc) is not related to the androgen-independent status (P = 0.09). On the other hand, neither FGFR1(IIIc) nor FGF2 and FGF7 have shown any significant variation in expression between normal and cancerous specimens. These findings propose that decreased expression of not only FGFR2(IIIb) but also FGFR2(IIIc) isoforms may be a critical step in prostate cancer progression and furthermore suggest that FGFR2(IIIb) expression could be used as a marker for prostate cancer evolution from androgen-dependent to androgen-independent status.
  The Prostate 08/2002; 52(3):245-52. · 3.48 Impact Factor
• Article: CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer.

  Alain Latil, Patrice Morant, Georges Fournier, Philippe Mangin, Philippe Berthon, Olivier Cussenot
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  ABSTRACT: Loss of heterozygosity (LOH) at chromosome 13q14 is one of the most recurrent anomalies observed in sporadic prostate tumors. This LOH is believed to unmask recessive mutations that inactivate a tumor-suppressor gene(s) which otherwise regulates normal cell growth and suppresses abnormal cell proliferation. Identification of potential tumor-suppressor genes within the deleted region is a way of indicating putative pathways of prostate cancer development and progression. The main target that disappears or is downregulated as a result of 13q14 loss remains to be identified. Therefore, our first concern was to find a gene located in the 13q14 region whose transcription is reduced. CHC1-L, for chromosome condensation 1-like, is mapped to the smallest common deleted region. CHC1-L expression is significantly reduced in prostate tumors compared to normal prostate tissues (p = 0.0002). In 21 of 36 (58%) primary prostate tumors studied, CHC1-L expression was reduced at least 2-fold, as measured by real-time quantitative RT-PCR; 18 of the tumors (50%) showed 13q14 LOH for at least 1 of the 5 polymorphic markers that we studied in the region, and 14 (78%) of these were among the tumors underexpressing CHC1-L. CHC1-L is alternatively spliced at its 5' end to produce 2 isoforms, of 551 and 526 aa. Analyses of CHC1-L integrity and of the quantitative expression of its variants indicate that the observed underexpression in prostate tumors is related to reduced expression of the 551 aa isoform. Although CHC1-L is not the obvious candidate given its only known homology, to RCC1, a guanine nucleotide exchange factor for the Ras-related GTPase Ran, the frequent significant decrease observed in its expression in prostate cancer associated with the difference in frequency of CHC1-L variant isoforms between normal and neoplastic prostate tissues places it in a pivotal role or possibly adjacent to a gene that has that role in prostate cancer evolution.
  International Journal of Cancer 07/2002; 99(5):689-96. · 5.44 Impact Factor