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. Lynch syndrome, microsatellite instability Introduction High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancers (CRCs) and results from defects in the DNA mismatch repair system (MMR). MSI-H CRCs accumulate numerous insertion/deletion mutations at short repetitive DNA sequences, termed microsatellites [1C3]. MSI-H CRCs may develop sporadically or in the context of the hereditary non-polyposis colorectal cancer (HNPCC) or JNJ-10397049 Lynch syndrome [4,5]. Clinically, they are characterized by a better prognosis and a lower frequency of distant metastases as compared to microsatellite stable CRCs [6]. A dense infiltration with lymphocytes is usually a typical feature of MSI-H CRCs, suggesting a pronounced JNJ-10397049 immunogenicity [7C10]. The immunogenicity of MSI-H CRCs is usually attributed to a wealth of frameshift prediction of FSP antigens provided the basis for detailed analyses that revealed a high frequency of FSP-specific T cell responses in patients with MSI-H JNJ-10397049 CRC and healthy Lynch syndrome mutation carriers [14], thus confirming that FSPs predicted in fact are relevant tumor antigens in vivo. The detection of humoral immune responses against FSPs may provide the basis for a serological test to identify or monitor patients with MSI-H tumors or Lynch syndrome. Against classical tumor antigens like p53, Her2/neu, or NY-ESO-1, serum antibody frequencies ranged between 10 and 20% [15]. The prevalence of humoral immune responses against FSPs has not been analyzed so far. Up to now, there is only an anecdotal report on antibodies specific for one FSP in a single patient suffering from a Lynch syndrome-associated CRC [16]. MSI-H CRC represents an ideal tumor entity for studying tumor antigen-specific humoral immune responses and designing serum antibody assays JNJ-10397049 because the abundance of FSPs and their predictability by bioinformatics. The present cross-sectional study is the first step towards a comprehensive systematic evaluation of FSP-specific antibodies in MSI-H CRC patients, healthy Lynch syndrome mutation carriers, and healthy controls. Materials and Methods Patients and healthy controls A total number of 152 sera were analyzed for antibodies against FSPs, obtained from 69 Lynch syndrome patients with history of MSI-H CRC (termed MSI-H CRC patients), 31 healthy Lynch syndrome mutation carriers and 52 healthy controls. Controls were age- and gender-matched to the MSI-H CRC patients. The median age of the patients was 50 years, of the mutation carriers 38 years and of the healthy controls 48 years (Table 1). Sera from MSI-H CRC patients and Lynch syndrome mutation carriers were collected at the University Hospitals of Heidelberg and Munich, Germany in the framework of the German HNPCC Consortium funded by the Deutsche Krebshilfe. Time after tumor resection in the MSI-H CRC patients was between 2 months and 16 years with a median of 3.6 years (interquartile range 1.8 to 6.0 years) (Table 1). Healthy Lynch syndrome mutation carriers took part in a clinical surveillance program (yearly colonoscopy and, where applicable, gynecologic examination), and only individuals without evidence for any cancer or preneoplastic lesion were included in this group. Healthy control sera were obtained from anonymized specimens of occupational employee examinations performed at the University Hospital of Mannheim, Germany. Sera were stored at ?70C in aliquots to minimize freeze-thaw cycles. All procedures were approved by the institutional ethics committee. Table 1 MSI-H CRC patients, healthy Lynch syndrome mutation carriers and healthy controls.
total n693152median age (years)503848age range28C7825C7527C80% male61.841.961.0
UICC stage110 (14.5%)–220 (29.0%)–314 (20.3%)–unknown25 (36.2%)–
time after Rabbit Polyclonal to HOXD12 tumor resection??2 months5 (7.2%)–??3 months to 12 months7 (10.1%)–??13 months.