[Molecular characterization of Lynch syndrome in Tunisia]. / Carastérisation moléculaire des mutations germinales et somatiques associées au cancer colorectal héréditaire sans polyposes en Tunisie.

BACKGROUND: High rates of early colorectal cancers (CRC) are observed in Tunisia suggesting genetic susceptibility. Nevertheless, up to now no molecular studies have been performed in the Tunisian population. AIM: To evaluate the clinical and genetic characteristics of Tunisian families suspected of hereditary nonpolyposis colorectal cancer (HNPCC) and to identify new tumoral markers for CRC susceptibility leading to distinguish patients with sporadic CRC from those with familial CRC, like HNPCC. METHODS: 31 unrelated families suspected of HNPCC were screened for germline mutations in MMR genes. We have also analyzed tumoral phenotype and the genetic characteristics of tumors from 51 patients with CRC meeting the Bethesda criteria. RESULTS: 10 different germ line mutations, 8 of which were novel, were identified in 11 out of the 31 families (35.5%), 5 in MSH2 and 5 in MLH1. Our results showed that MUC5AC expression was more frequent in patients with family history of CRC (p=0.039). CONCLUSION: The analysis of MUC5AC expression might be very beneficial in the detection of Tunisian patients with high susceptibility to CRC.

KRAS mutation detection in Tunisian sporadic coloractal cancer patients with direct sequencing, high resolution melting and denaturating high performance liquid chromatography.

The Kirsten Rat Sarcoma (KRAS) oncogene has been introduced recently as a genetic biomarker for metastatic sporadic colorectal cancer prior to anti-EGFR treatment. Identifying patients with KRAS mutations that not respond to EGFR targeted therapies require sensitive, rapid and efficacious routine technique. We have attempted to evaluate the efficiency of three conventional methods: direct sequencing, HRM and DHPLC, to detect mutations in codon 12 and 13 of the KRAS exon2 gene. For this first Tunisian study on KRAS, we detected 45.83% of altered KRAS gene among 48 formalin-fixed paraffin-embedded sporadic colorectal adenocarcinoma patients. The use of HRM-sequencing allowed as enlarging the detected KRAS exon 2 mutations (22/48) in comparison with direct sequencing (17/48). DHPLC was used to confirm results when consensus was not observed between HRM and direct sequencing. This study brings an interesting data concerning an inter-method validation between sequencing and HRM in the investigation of sporadic colorectal cancer biomarker. It also shows that KRAS mutations occur at similar frequencies in Tunisian patients as in other populations; and suggests that the same genes are at play in sporadic CRC cancer, despite ethnic, geographical and environmental differences between countries.