Biomedical subjects

Georges Fournier

Publications and source records attributed to Georges Fournier.

14 recordsLinked to original sources

PubMed2005

Differential expression of 37 selected genes in hormone-refractory prostate cancer using quantitative taqman real-time RT-PCR.

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.

Androgens↗

PubMed2005

Testicular adrenal rest tumours in salt wasting congenital adrenal hyperplasia (in vivo and in vitro studies).

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.

Adrenal Hyperplasia, Congenital↗

PubMed2005

[Idiopathic acute partial renal infarction].

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.

Acute Disease↗

PubMed2004

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.

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.

Carcinoma, Transitional Cell↗

PubMed2004

Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer.

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 ). CONCLUSIONS: 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.

Adult↗

PubMed2004

Molecular profiling of benign prostatic hyperplasia using a large scale real-time reverse transcriptase-polymerase chain reaction approach.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗

PubMed2003

Extensive analysis of the 13q14 region in human prostate tumors: DNA analysis and quantitative expression of genes lying in the interval of deletion.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Adenocarcinoma↗

PubMed2003

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.

Adenocarcinoma↗

PubMed2003

Familial prostate cancer cases before and after radical prostatectomy do not show any aggressiveness compared with sporadic cases.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Follow-Up Studies↗

PubMed2003

[Effect of bicalutamide 150 mg, after 3 years of median follow-up, in non-metastatic prostatic cancer].

OBJECTIVE: To determine the efficacy and safety of bicalutamide, at the dose of 150 mg per day, as first-line monotherapy or as curative adjuvant therapy in patients with non-metastatic prostate cancer, and to investigate the possibility of a greater benefit for certain patient subgroups. MATERIAL AND METHODS: This article recalls the preliminary results of an international endocrine therapy programme comprising three double-blind placebo-controlled clinical trials in patients with non-metastatic prostate cancer (T1-T4. Nx/N0/N1, M0). Patients were randomized to receive either 150 mg/day of bicalutamide, or placebo, as an adjuvant to radical prostatectomy, external beam radiotherapy or in the context of watchful waiting. The main endpoints were the time to objective clinical progression and overall survival. The combined data of the three trials were submitted to intent-to-treat analysis. The authors also report the results of exploratory studies performed as a function of the type of treatment and prognostic factors. RESULTS: After a median follow-up of 3 years of a sample size of 8,113 patients, objective clinical progression was observed in 9% of patients of the bicalutamide group (4,052 patients) and in 13.8% of patients of the placebo group (4,061 patients), corresponding to a 42% relative risk reduction (RR: 0.58; p << 0.0001). Reduction of the risk of disease progression was observed for the entire study population regardless of primary treatment, stage of disease or usual prognostic factors. This reduction was more marked for patients presenting poor prognostic factors. Data concerning overall survival are not available due to insufficient follow-up. Treatment was well tolerated. The adverse effects most frequently reported in the bicalutamide group were gynaecomastia and breast pain. CONCLUSION: After a median follow-up of three years, bicalutamide, as first-line monotherapy or as curative adjuvant therapy, significantly reduced the risk of objective clinical disease progression in patients with non-metastatic prostate cancer. Exploratory analyses demonstrate that the benefit of bicalutamide appeared to be greater for patient with poor prognostic factors. Survival data are not yet available.

Adult↗

PubMed2002

Down-regulation of (IIIb) and (IIIc) isoforms of fibroblast growth factor receptor 2 (FGFR2) is associated with malignant progression in human prostate.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cell Line↗

PubMed2002

CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer.

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.

Alleles↗

PubMed2002

Worry and attitude of men in at-risk families for prostate cancer about genetic susceptibility and genetic testing.

BACKGROUND: The aim of this study was to evaluate worry about genetic susceptibility and the attitude of men with family history of prostate cancer (CaP) toward genetic testing. METHODS: Three hundred seventy-five eligible first-degree relatives (FDR) of men with CaP, were asked to participate in a screening and to fill out a survey covering the worry about genetic susceptibility and interest in genetic testing. RESULTS: Of the 375 candidates contacted, 277 completed the survey, and had undergone PSA measurement. Sixty-four percent worried a little or not at all about inherited predisposition to CaP, while the remainder worried a lot or extremely. The candidates who worried a lot or extremely were men with high levels of durable anxiety disposition (STAI trait), who had undergone a previous screening procedure and men with sons. Ninety-eight percent of men expressed their interest in undergoing genetic testing. The most motivated candidates to have the test done were men with several relatives with CaP. CONCLUSIONS: The level of worry about genetic susceptibility was low and there was a concrete interest in genetic testing in FDR of men with CaP. This interest increased with the number of CaP in the family.

Adult↗

PubMed2002

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Androgens↗