Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome.
High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.
Reuschenbach
Miriam
M
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany.
Kloor
Matthias
M
Morak
Monika
M
Wentzensen
Nicolas
N
Germann
Anja
A
Garbe
Yvette
Y
Tariverdian
Mirjam
M
Findeisen
Peter
P
Neumaier
Michael
M
Holinski-Feder
Elke
E
von Knebel Doeberitz
Magnus
M
D000906:Antibodies / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000150:complications / Q000276:immunology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000276:immunology; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010455:Peptides / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D010455:Peptides; D051718:MutS Homolog 2 Protein