Frequent mutations of the CA simple sequence repeat in intron 1 of EGFR in mismatch repair-deficient colorectal cancers.

AIM: To investigate the polymorphic simple sequence repeat in intron 1 of the epidermal growth factor receptor gene (EGFR) (CA-SSR I), which is known to affect the efficiency of gene transcription as a putative target of the mismatch repair (MMR) machinery in colorectal tumors. METHODS: The CA-SSR I genotype was analyzed in a total of 86 primary colorectal tumors, selected upon their microsatellite instability (MSI) status [42 with high frequency MSI (MSI-H) and 44 microsatellite stable (MSS)] and their respective normal tissue. The effect of the CA-SSR I genotype on the expression of the EGFR gene was evaluated in 18 specimens using quantitative real-time reverse transcription PCR and immunohistochemistry. RESULTS: Mutations in CA-SSR I were detected in 86% (36 of 42) of MSI-H colorectal tumors and 0% (0 of 44) of MSS tumors, indicating the EGFR gene as a novel putative specific target of the defective MMR system (P < 0.001). Impaired expression of EGFR was detected in most of the colorectal tumors analyzed [6/12 (50%) at the mRNA level and 15/18 (83%) at the peptide level]. However, no association was apparent between EGFR expression and CA-SSR I status in tumors or normal tissues. CONCLUSION: Our results suggest that CA-SSR I sequence does not contribute to the regulation of EGFR transcription in colon, and should thus not be considered as a promising predictive marker for response to EGFR inhibitors in patients with colorectal cancer.

[von Hippel-Lindau syndrome: molecular diagnosis of two Lebanese families and analysis of the genotype-phenotype correlation]. / La maladie de von Hippel-Lindau: Etude moléculaire de deux families libanaises et analyse de la corrélation génotype-phénotype.

The von Hippel-Lindau syndrome (VHL) is a dominantly transmitted hereditary disorder associating multisystemic tumors affecting mainly the central nervous system, the kidneys, the pancreas, as well as pheochromocytomas. Mutations of the tumor suppressor gene VHL on chromosome 3 are responsible for the disease. This article reports for the first time the study of two Lebanese VHL affected families, presenting particularly hemangioblastomas of the central nervous system. Two different mutations of the VHL gene, S65W and F76S, respectively identified in the two families, confirmed the clinical diagnosis of the patients. Molecular diagnosis was then performed for at risk members of these families. This article reveals the importance of molecular diagnosis for suspected patients and of presymptomatic diagnosis for at risk members, especially that a close follow-up of carriers allows an early detection of tumors and prevents the metastasis stage, the most common cause of death of these patients.