Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations.
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.
Tougeron
David
D
Inserm, U614, Faculty of Medicine, Institute for Medical Research, Rouen, Northwest Cancéropôle, France.
Fauquembergue
Emilie
E
Rouquette
Alexandre
A
Le Pessot
Florence
F
Sesboüé
Richard
R
Laurent
Michèle
M
Berthet
Pascaline
P
Mauillon
Jacques
J
Di Fiore
Frédéric
F
Sabourin
Jean-Christophe
JC
Michel
Pierre
P
Tosi
Mario
M
Frébourg
Thierry
T
Latouche
Jean-Baptiste
JB
D030301:Activin Receptors, Type II / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016368:Frameshift Mutation; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics
D035463:Pol1 Transcription Initiation Complex Proteins; D018125:Receptors, Transforming Growth Factor beta; C091129:TAF1B protein, human; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human