Signature of microsatellite instability, KRAS and BRAF gene mutations in German patients with locally advanced rectal adenocarcinoma before and after neoadjuvant 5-FU radiochemotherapy.

BACKGROUND: Multiple activating mutations of the signal- and repair pathway, such as BRAF-, KRAS-mutations and microsatellite instabilities are involved in colorectal cancer pathogenesis. Molecular characterization of specifically locally advanced rectal cancers is scarce. Therefore the retrospective study addresses the intratumoral status of KRAS, BRAF and microsatellites loci with respect to tumor response and patients' antecedent including nicotine abusus, familial history, and health care to further molecularly identify rectal cancer patients.
METHODS: The study assesses the molecular status of 50 rectal cancer samples (25 before and 25 after neoadjuvant 5-FU radiochemotherapy). KRAS and BRAF mutations were examined through two independent analytical methods (sequencing and SNaPshot) to ensure efficient mutation detection. The microsatellite analysis was conducted using a fluorescent multiplex PCR-based method.
RESULTS: KRAS mutations were found in 9 of 25 (36%) rectal cancer patients and were not significantly associated with the response to therapy (P=0.577), age (P=0.249) or sex of the patient (P=0.566). No link exists between KRAS mutation status and nodal (P=0.371) or metastatic stage (P=0.216). For two patients, KRAS mutation status changed after application of neoadjuvant 5-FU radiochemotherapy. All tumor samples were diagnosed BRAF-negative. Two rectal cancer patients exhibited a MSI-H phenotype and showed no tumor response.
CONCLUSIONS: So one can conclude that (I) KRAS mutations status may change after neoadjuvant 5-FU radiochemotherapy relevant for further therapeutic decisions; (II) MSI-H patients do not respond to neoadjuvant 5-FU radiochemotherapy. Further prospective studies are needed to validate these results.