Irene Vegh

Single Nucleotide Change in the Cannabinoid Receptor-1 (CNR1) Gene in Colorectal Cancer Outcome

The cannabinoid receptor-1 (CNR-1) and endogenous agonists of this receptor are present in the central and peripheral nervous systems including the gastrointestinal nervous system. The surgically rejected specimens of human colorectal cancers and paired normal tissues were studied to detect mutations in the CNR1 gene by sequencing method. The results were compared to clinicopathological parameters and correlated with overall survival time. Sixty-three colorectal cancer patients, who underwent surgical excision of colorectal carcinoma, were included in this study. The coding region of the CNR1 gene was studied: a nucleotide change (G→A) at position 1359 was identified by direct sequencing of PCR. Thirty-eight patients had the G/G genotype (wild type) in tumor areas and 25 patients had G/A heterozygous or A/A homozygous genotype. Univariate analysis revealed 2 independent variables associated with CNR1 gene mutation. The results show that the patients with Dukes stage C and D had a 2.9 times (p = 0.04) and patients that were lymph node positive had 2.8 times (p = 0.05) greater probability of nucleotide change in CNR1 gene. Genotype G/A plus A/A had a shorter overall survival time than G/G wild-type patients (p < 0.05). Indeed nontumor paired colorectal tissues showed nucleotide change. A large number of patients with mutation in the CNR1 gene were observed. These preliminary findings highlight the importance of further studies in the use of cannabinoid analogs as receptor ligands to analyze potential therapeutic effects.

Mutation in CNR1 gene and VEGF expression in esophageal cancer.

Aims and background Cannabinoid receptors have an impact on gastrointestinal function, but it remains unknown whether mutations may affect tumor susceptibility in patients with esophageal carcinoma. The aim of this study was to determine mutation in the cannabinoid receptor-1 (CNR1) gene and its relation to vascular endothelial growth factor (VEGF) expression as an angiogenic and poor prognostic factor. Methods 179 esophageal tissue samples from 69 patients (29 with esophageal cancer and 40 controls) were studied. CNR1 gene mutation (1359 G → A in codon 453) was detected with PCR, using the MspI restriction enzyme. VEGF was determined by immunoassay. Results Genotyping in control patients’ samples revealed that 24/40 were G/G wild type and 16/40 were G/A; no samples were A/A. Of the 139 tissue samples from the 29 esophageal cancer patients, 15 were G/G homozygous, 85 G/A heterozygous, 11 had an A/A genotype and 28 were without amplification. In the normal tissue adjacent to tumor, some mutations were observed. The overall survival time was reduced in patients with the A/A type in all their 5 samples, in comparison to G/G type (P = 0.04, chi-square: 4.26). VEGF expression was higher in tumor than nontumor areas (P <0.025). VEGF expression was not correlated with survival time. Conclusions Our preliminary findings in esophageal tissue showed a high frequency of G → A mutation in the CNR1 gene. No correlation between VEGF expression and gene receptor mutation was found. Patients with mutation in all their samples had a reduced survival time.

Relationship between biomarker expression and allelic alteration in esophageal carcinoma

Background and Aim:  Expression of biomarkers and probable allelic alterations were studied in esophagus tissue samples from patients with esophageal carcinoma.

Colorectal Cancer Relapse: Allelic Alterations Associated with Tumour Marker Overexpression

The objective of the present study was to assess the prognostic value of allelic alterations in comparison with clinical prognostic factors (age and gender, clinical stage, lymph node involvement, tissue tumour marker expression) and clinical outcomes (disease relapse and overall survival time) in colorectal cancer patients. Polymerase chain reaction was performed on the DNA of 72 colorectal samples (from 36 colorectal cancer patients) using primers D17S513 and D17S514. Carbohydrate antigen 19-9 (CA 19-9) marker was determined in tumour sections by enzyme immunoassay. Tumours were considered to exhibit allelic alterations if the microsatellite region adjacent to the p53 locus in chromosome 17 either gained or lost repeated sequences. Allelic alterations were detected in 44% of tumour samples. Patients with more than 3 involved lymph nodes had more frequent allelic alterations (p < 0.002). The allelic alteration status was compared with tumour CA 19-9 expression, which showed statistically significantly higher values within the allelic alterations group (p < 0.005). Multivariate analyses confirmed that tumours with allelic alterations had a higher probability of disease relapse (odds ratio 7.3, p = 0.01). This is the first report showing an association between allelic alteration and overexpression of a tissue tumour marker protein and established risk factors. These results could be considered useful additional prognostic information for colorectal cancer.

Biomarkers, Stem Cells and Esophageal Cancer

There are two main forms of esophagus cancer with different malignant behaviors: epidermal or squamous carcinoma (ESCC) and esophagus adenocarcinoma (EA). ESCC is associated with ethanol and tobacco consumption (tobacco-specific-Nnitroso compounds). ESCC is among the more aggressive cancers known. The high mortality rate associated with this type of cancer is directly related to a late diagnosis. Thus there is an important challenge to identify biomarkers for early diagnosis (Shimada et al., 2003; Sobin & Fleming, 1997).

In vivo effect of an luteinizing hormone-releasing hormone analog on vascular endothelial growth factor and epidermal growth factor receptor expression in mammary tumors

Background: The hypothalamic luteinizing hormone-releasing hormone (LHRH) is well known for its role in the control of pituitary gonadotropin secretion and it has demonstrated a direct antiproliferative effect on some cancer cell lines of LHRH and its synthetic analogs. The study was designed to assess whether administration of the LHRH analog (goserelin) has any effect on the expression of the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) in rats with N-nitroso-N-methylurea (NMU)-induced-mammary tumors “in vivo” Materials and Methods: The animals with tumors were assessed after acute or chronic treatment with goserelin, and in all the animals VEGF and EGFR expression was examined both in plasma and tumor homogenates by enzyme immunoassay. Results: The basal plasma values of VEGF were lower in the healthy control group than in rats with NMU-induced tumors (P = 0.025). Following acute treatment with goserelin, VEGF expression in plasma increased above basal levels after 60 min (P = 0.05) and dropped during chronic treatment. Likewise, in the tumor homogenate the mean VEGF expression was higher at 60 min post-goserelin administration than the basal levels, although VEGF expression then diminished at 90 min. Plasma EGFR expression was higher in rats with NMU-induced tumors than in healthy controls (P<0.01). Conclusions: The results allow us to conclude that goserelin may exert a short-term stimulatory effect on the release of VEGF, as well as a long-term inhibitory effect on VEGF but not EGFR expression.

Contents Vol. 76, 2009

A.B. Benson, Chicago, Ill. A.Y. Chang, Singapore A.-L. Cheng, Taipei J.F. Cleary, Madison, Wisc. M.S. Ernstoff , Lebanon, N.H. J.J. Grau, Barcelona D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buff alo, N.Y. M.J. Kelley, Durham, N.C. P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buff alo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Curacao D. Raghavan, Cleveland, Ohio E.A. Repasky, Buff alo, N.Y. C.N. Sternberg, Rome R. Stupp, Lausanne M.S. Tallman, Chicago, Ill. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buff alo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief