1. ¹Inserm, U614, Faculty of Medicine, Institute for Medical Research, Rouen, Northwest Cancéropôle, France
2. ²Digestive Oncology Unit, Department of Gastroenterology, University Hospital, Rouen, Northwest Cancéropôle, France
3. ³Department of Pathology, University Hospital, Rouen, Northwest Cancéropôle, France
4. ⁴Department of Genetics, CRLCC François Baclesse, Caen, Northwest Cancéropôle, France
5. ⁵Department of Genetics, University Hospital, Rouen, Northwest Cancéropôle, France

Correspondence: Dr JB Latouche, MD, PhD, Inserm, U614, Faculty of Medicine, 22 Boulevard Gambetta, Rouen, Cedex 76183, France. E-mail: jean-baptiste.latouche@chu-rouen.fr

Received 2 March 2009; Revised 22 April 2009; Accepted 23 April 2009; Published online 5 June 2009.

Abstract

Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3+ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.