A gene expression and pre-mRNA splicing signature that marks the adenoma-adenocarcinoma progression in colorectal cancer.

It is widely accepted that most colorectal cancers (CRCs) arise from colorectal adenomas (CRAs), but transcriptomic data characterizing the progression from colorectal normal mucosa to adenoma, and then to adenocarcinoma are scarce. These transition steps were investigated using microarrays, both at the level of gene expression and alternative pre-mRNA splicing. Many genes and exons were abnormally expressed in CRAs, even more than in CRCs, as compared to normal mucosae. Known biological pathways involved in CRC were altered in CRA, but several new enriched pathways were also recognized, such as the complement and coagulation cascades. We also identified four intersectional transcriptional signatures that could distinguish CRAs from normal mucosae or CRCs, including a signature of 40 genes differentially deregulated in both CRA and CRC samples. A majority of these genes had been described in different cancers, including FBLN1 or INHBA, but only a few in CRC. Several of these changes were also observed at the protein level. In addition, 20% of these genes (i.e. CFH, CRYAB, DPT, FBLN1, ITIH5, NR3C2, SLIT3 and TIMP1) showed altered pre-mRNA splicing in CRAs. As a global variation occurring since the CRA stage, and maintained in CRC, the expression and splicing changes of this 40-gene set may mark the risk of cancer occurrence from analysis of CRA biopsies.

VEGFR1 and NRP1 endothelial expressions predict distant relapse after radical prostatectomy in clinically localized prostate cancer.

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.

Trends in incidence, management, and survival of gastric and cardia carcinomas in the area of Finistere (France) between 1984 and 2003.

OBJECTIVE: The aim of this study was to evaluate trends in incidence and prognosis of gastric and cardia carcinomas in the area of Finistère (France) between 1984 and 2003. METHODS: The Digestive Tumor Registry of Finistère recorded all new cases of gastric and cardia carcinomas from January 1, 1984 to December 31, 2003. Raw incidence data were standardized using the direct method based on the reference world population. The data and survival rates were studied in univariate and multivariate analyses. RESULTS: Between 1984-1988 and 1999-2003 the standardized incidence of distal gastric carcinomas decreased (10.74 ± 0.39-5.68 ± 0.27/year/100 000 inhabitants, P < 0.001). There was no significant increase in the incidence of cardia carcinomas (0.83 ± 0.11-1.25 ± 0.14/year/100 000 inhabitants). The frequency of macroscopically infiltrating tumors doubled (P < 0.001) and linitis plastica increased from 9 to 16.2% (P < 0.001). Overall survival rates increased only for patients with metastatic carcinomas of both locations (P < 0.001) and with advanced tumors of distal stomach (P < 0.001) receiving therapy. CONCLUSION: This study showed a significant decrease over time in the incidence of distal gastric carcinomas but no significant increase in the incidence of cardia carcinomas. Despite improvement in the management of patients, prognosis remains dismal, probably because of an increased incidence of poor prognosis of histological and anatomical types.

Positive VEGF immunostaining independently predicts poor prognosis in curatively resected gastric cancer patients: results of a study assessing a panel of angiogenic markers.

Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) contribute to gastric cancer aggressiveness by up-regulating the expression of proteases. We evaluated the expression and the prognostic significance of angiogenic factors and proteases in 148 patients with R0-resected gastric cancer. Expression of VEGF, Ang-2, cyclooxygenase-2 (COX-2), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1, matrix metalloproteinases (MMP)-1 and -9 were assayed by immunohistochemistry. After a mean of 63 +/- 4 months, 81 out of 148 patients had died due to disease. The probability of being free of recurrence was 62, 48, and 42% at 2, 5, and 10 years, respectively. Single bivariate analysis identified VEGF, Ang-2, COX-2, PAI-1, and MMP-9 expression, along with several clinicopathological parameters (grade of curability, lymph node ratio, pTNM, pT, pN), as variables associated with both decreased disease-specific survival and recurrence. On multivariate analysis, after adjusting for significant clinical covariables, positive VEGF immunostaining was the primary prognostic factor, and no other tumor marker variable could add any significant improvement for the prediction, for both disease-specific survival (p = 0.001; HR, 3.27; 95% CI, 1.76 to 6.10) and tumor recurrence (p = 0.002; HR, 2.81; 95% CI, 1.48 to 5.35). Our study suggests that VEGF alone may be clinically useful for establishing therapeutic decisions in gastric cancer patients.

Prevalence and topography of intestinal metaplasia in columnar lined esophagus.

OBJECTIVES: Barrett's mucosa is considered as a mosaic of three epithelial types but little is known about the topography of intestinal metaplasia in columnar lined esophagus. The aims of the study were to determine the prevalence of intestinal metaplasia within long and short segments of columnar lined esophagus and to analyze the distribution of the intestinal metaplasia within long segments of Barrett's esophagus. PATIENTS AND METHODS: The study was performed on the initial endoscopy carried out among 112 patients enrolled in an endoscopic surveillance program. Seventy-two patients with columnar mucosa extending more than 3 cm into the esophagus (group I) and 40 patients with a short segment of columnar mucosa (group II) had multiple biopsies according to a standardized protocol. 1163 biopsies were analyzed on the whole: 949 biopsies in group I and 214 biopsies in group II. RESULTS: Intestinal metaplasia was identified among 650 (68.5%) and 50 (23.4%) biopsies in groups I and II respectively (P<10-7). The proportion of biopsies with foci of intestinal metaplasia increased significantly with the length of the columnar mucosa. The diagnosis of Barrett's esophagus was confirmed in 100% of the patients in group I and in 45% of the patients in group II. In long segments of Barrett's esophagus, intestinal metaplasia was more frequently observed in the 2 upper thirds of the columnar mucosa that in the lower third (P<10-7). Detailed mapping of the distribution of epithelial types within the columnar lined esophagus identified three patterns of distribution of intestinal metaplasia within long segments of Barrett's esophagus: unifocal, multifocal and diffuse, in 5%, 56% and 39% of the patients respectively. Dysplasia was present in 15% of patients with long segments of Barrett's esophagus and 11% of patients with short segments (NS). CONCLUSION: The distribution of intestinal metaplasia within columnar lined esophagus is heterogeneous and three distinct patterns can be identified: unifocal, multifocal and diffuse. Considering the risk of sampling error, the current recommendations concerning the biopsy protocols are mandatory until the validation of new techniques such as chromoendoscopy or magnifying endoscopy.

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.

Infrequent p16/CDKN2 alterations in squamous cell carcinoma of the oesophagus.

Loss of heterozygosity (LOH) on chromosome 9 and p16 (MTS1/CDKN2) gene mutations have been reported in various human cancers. The present study aimed to determine the prevalence of LOH in 100 oesophageal squamous cell carcinomas (OSCCs) by typing microsatellite loci and mutations of the p16 gene. The methods used included denaturing gradient gel electrophoresis (DGGE) and DNA sequencing of exon 2. LOH was found in 14.7% of the OSCC cases. Six gene alterations were identified in exon 2. They consisted of three deletions and the same polymorphism in three samples. The relatively low rate of p16 mutation compared with the frequency of LOH suggests the possible involvement of another tumour suppressor gene located on chromosome 9 in oesophageal carcinogenesis.