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A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up

¹ Department of Clinical Medicine, St James’s Hospital, Dublin, Ireland
² Department of Molecular Medicine, St James’s Hospital, Dublin, Ireland
³ Laboratoire de Biotechnologie et Génétique Appliquée, Ecole d’Ingénieurs HES de Lullier, 1254 Jussy, Switzerland

Correspondence to:
Dr B Ryan, Department of Gastroenterology, University Hospital Maastricht, PO Box 5800, 6202AZ, Maastricht, the Netherlands;
bbryan{at}planet.nl

Background and aims: Mutant tumour derived DNA has been detected in the sera of colorectal cancer patients. We investigated if mutant serum KRAS2 was detectable preoperatively in a large group of patients with colorectal neoplasia. A prospective study of 94 patients who underwent putative curative resection for colorectal carcinoma (CRC) was performed to ascertain if serum mutant KRAS2 could be used postoperatively as a disease marker.

Methods: Preoperative sera from 78 patients were analysed (group A). Sera from 94 patients were obtained three monthly for up to three years during the postoperative period (group B). Codon 12 and 13 KRAS2 mutations were analysed in matched tumour and serum samples.

Results: In the preoperative group (group A), KRAS2 mutation was found in 41/78 (53%) tumours and in 32/78 (41%) preoperative sera. Of 41 tumour KRAS2 mutation positive cases, 31/41 (76%) had an identical serum mutation detectable. In group B, the postoperative follow up group, 60/94 cases were primary tumour KRAS2 mutation positive. Of these 60, 16/60 (27%) became persistently serum mutant KRAS2 positive postoperatively. Ten of 16 (63%) of these developed a recurrence compared with only 1/44 (2%) patients who remained serum mutant negative (odds ratio 71.7 (95% confidence interval 7.7–663.9; p=0.0000). None of 34 tumour mutation negative cases became serum mutant KRAS2 positive postoperatively, despite recurrence in 9/34 patients. The relative hazard of disease recurrence in postoperative serum mutant KRAS2 positive patients was 6.37 (2.26–18.0; p=0.000).

Conclusions: Serum mutant KRAS2 can be detected preoperatively in all stages of colorectal neoplasia. Postoperatively, serum mutant KRAS2 is a strong predictor of disease recurrence, stronger even than Dukes’ stage of disease, and thus shows potential for use in clinical practice as a marker of preclinical disease recurrence.

Keywords: DNA; KRAS2; KRAS2 mutation; prognosis; colorectal carcinoma

Abbreviations: CRC, colorectal carcinoma; TVA, tubulovillous adenoma; CEA, carcinoembryonic antigen; OR, odds ratio; PCR, polymerase chain reaction