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Immunology |
Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M. J. S., S. W., C. M. G., Y-T. C., A. O. G., E. S., A. A. J., G. R., L. J. O.]; Weill Medical College of Cornell University, Department of Pathology, New York, New York 10021 [Y-T. C., D. J.]; and II.Medizinische Klinik, Hämatologie-Onkologie, Krankenhaus Nordwest, 60488 Frankfurt, Germany [D. J., E. J., A. K.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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fetoprotein in hepatoma and germ cell tumors, CA125 in ovarian cancer, and prostate-specific antigen in prostate cancer (1)
. Convincing evidence now exists that the humoral immune system of cancer patients recognizes tumor-related antigens (2, 3, 4, 5, 6)
. In contrast to the detection of serum antigens, the detection of serum antibody responses to tumor antigens could represent a novel form of serum marker for cancer diagnosis (7, 8, 9, 10)
. The structural definition of the antigenic targets recognized by serum antibody in cancer patients has been revolutionized by the development of an expression cloning strategy termed SEREX3
(4)
. To date, >1000 different immunogenic tumor products have been defined by SEREX analysis of a wide range of tumor types (reviewed in Ref. 11
; see SEREX database4
). SEREX analysis (7 , 8 , 12 , 13) has defined a subset of tumor antigens that react exclusively with serum antibodies derived from multiple cancer patients but do not react with sera from normal individuals. Serum antibodies detecting this subset of tumor antigens represent potentially valuable serum markers for cancer. For example, previous SEREX analysis of renal cancer has led to the identification of 12 antigens associated with a cancer-related serological response in which 72% of serum samples from renal cancer patients had serum antibodies to at least one of these antigens, whereas sera from normal individuals did not (8) .
A pattern of cancer-related serological recognition of tumor antigens suggests a common immunogenic stimulus, e.g., the antibody response to mutated p53 tumor suppressor protein in colon, breast, and lung cancer patients (14) . Changes in the level of gene expression in cancer (3 , 6 , 9 , 12) and aberrant expression of tissue-restricted gene products in cancer (15, 16, 17) have also been related to the development of a humoral immune response in cancer patients. Tumor antigens that are associated with both aberrant expression and cancer-related antibody recognition represent attractive targets for antigen-specific cancer vaccines. In this category are the CT antigens, such as NY-ESO-1, which are normally expressed in germ cells and aberrantly expressed in many tumor types (15 , 18, 19, 20, 21) . NY-ESO-1 elicits a strong humoral (13) and cellular immune response (22) and is being developed as a cancer vaccine target (23) .
To evaluate the seroreactivity of many SEREX-defined antigens, a method for in block testing of antibody reactivity to >100 tumor antigens was recently developed and termed the SADA (or spot immunoassay; Ref. 12 ). In this study, this method has been used to evaluate the serological response of 74 colon cancer patients and 75 normal individuals to a panel of 77 SEREX-defined antigens. A subset of 8 antigens was found to be associated with both a colon cancer-related serological response and altered mRNA expression in colon cancer. On the basis of cancer-related immunogenicity, restricted expression in normal tissues, and overexpression in colon cancer, one of these antigens, NY-CO-58/KNSL6, has potential as both an immunotherapeutic and a diagnostic target.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ZAPII cDNA expression library from the Colo205 colon cancer cell line (Stratagene, La Jolla, CA) and a TRIPLX cDNA expression library from normal human testis (Clontech, Palo Alto, CA) were obtained commercially. A third cDNA expression library was prepared in the ZAPexpress vector (Stratagene) according to manufacturer’s instructions using 5 µg of polyA+ mRNA obtained from the HT29 colon cancer cell line. Sera from 2 colon cancer patients were preabsorbed as previously described (7 , 8) to remove antibodies that react with the vector system. The three cDNA expression libraries were immunoscreened by SEREX methodology (4 , 7) at a pooled serum dilution of 1:100 (1:200 individual serum dilution), a dilution previously shown to provide a low signal:noise ratio (7 , 8 , 12 , 15) . A total of 5–6 x 105 recombinants were screened/cDNA library. Serum reactive phage clones were converted to plasmid forms and subjected to DNA sequencing (Cornell University DNA Services, Ithaca, NY).
SADA for Analyzing Serum Reactivity.
Preabsorbed serum samples (7
, 8)
from 74 patients with colon cancer and 75 healthy blood donors were evaluated by SADA (12)
for the presence of IgG antibody to a panel of 77 SEREX-defined antigens. Briefly, precut nitrocellulose membranes (80 x 120 mm) were precoated with a layer (
0.2 mm) of growth media (NZY/0.7% agarose/2.5 mM isopropyl-ß-D-thiogalactopyranoside) and placed on a reservoir layer of NZY/0.7% agarose in a 86 x 128 mm Omni Tray (Nalge Nunc International Corp., Naperville, IL). A total of 1.0 x 105 pfu of bacteriophage encoding individual SEREX-defined tumor antigens in a volume of 20 µl was mixed with 20 µl of exponentially growing Escherichia coli XL-1 Blue MRF’ and spotted (0.7-µl aliquots) on the precoated nitrocellulose membranes. Thirty SEREX-defined antigens were spotted in duplicate on each nitrocellulose membrane. Membranes were incubated for 15 h at 37°C and then processed as per the standard SEREX protocol (7
, 8)
, i.e., blocked in 0.5% nonfat dried milk, incubated in 10 ml of a 1:200 dilution of sera at room temperature for 15 h, and then incubated in a 1:3000 dilution of alkaline phosphatase conjugated, Fc fragment-specific, goat antihuman IgG (Jackson Immunoresearch laboratories Inc., West Grove, PA). Serum IgG reactivity was detected with the alkaline phosphatase substrate, 4-nitro blue tetrazolium chloride/5-bromo-4-chloro-3-indolyl-phosphate.
Real-time Quantitative RT-PCR.
Total RNA samples from 9 cases of colon cancer and 8 normal colon specimens were prepared by the guanidinium thiocyanate method. Gene-specific TaqMan probes and PCR primers were designed using Primer Express software (PE Biosystems, Foster City, CA). RNA (1.0 µg) was reverse transcribed using the TaqMan EZ RT-PCR kit (PE Biosystems). Multiplex PCR reactions were prepared using 2.5 µl of cDNA diluted in TaqMan PCR Master Mix supplemented with Vic (PE Biosystems proprietary dye)-labeled human ß glucuronidase endogenous control probe/primer mix, 200 nM FAM-labeled gene-specific TaqMan probe, and a predetermined, optimum concentration of gene-specific forward and reverse primers (300–900 nM). Triplicate PCR reactions were prepared for each cDNA sample. PCR consisted of 40 cycles of 95°C denaturation (15 s) and 60°C annealing/extension (60 s). Thermal cycling and fluorescent monitoring were performed using an ABI 7700 sequence analyzer (PE Biosystems). The point at which the PCR product is first detected above a fixed threshold, termed cycle threshold (Ct), was determined for each sample.
To determine the quantity of gene-specific transcripts present in colon cancer cDNA relative to normal colon, their respective Ct values were first normalized by subtracting the Ct value obtained from the glucuronidase endogenous control (
Ct = Ct FAM - Ct VIC). The concentration of gene-specific mRNA in colon cancer relative to normal colon was calculated by subtracting the normalized Ct values obtained with normal colon from those obtained with tumor samples (Ct = Ct of tumor - Ct of normal colon), and the relative concentration was determined (relative concentration = 2-Ct. The mean relative concentration was derived from 8 normal colon tissue samples.
The concentration of gene-specific transcripts in normal tissues was also measured by real-time RT-PCR using 16 different normal tissue cDNA preparations that had been normalized for six housekeeping genes (Clontech). The Ct values were measured, and the average Ct of triplicate samples was calculated. The abundance of gene-specific transcripts in normal tissues was determined by comparison with a standard curve generated from the Ct values of known concentrations of plasmid DNA template encoding the relevant gene product.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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are associated with a colon cancer-related serological response. The remaining 64 antigens reacted only with the serum sample used in their original SEREX isolation, or with sera from healthy donors, and were excluded from additional analysis. Of the 13 antigens having a cancer-related serological profile, 4 are known tumor-related antigens, including 3 CT antigens (MAGEA3, SSX-2, and NY-ESO-1; Refs. 4
, 15
, 19
) and the p53 tumor suppressor protein (7
, 14)
. Four other antigens (NY-CO-9/HDAC5, NY-CO-41/MBD2, NY-CO-42/TRIP4, and NY-CO-95/KIAA1416; Refs. 7
, 25, 26, 27, 28
) may be involved in the regulation of DNA transcription, and the remaining 5 antigens (NY-CO-45, NY-CO-58, NY-CO-61, NY-CO-94, and NY-REN-32) have no known or suspected association with cancer.
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, 34 of 74 colon cancer patients (46%) had serum IgG antibodies that reacted with at least 1 of the 13 antigens. In this subset of seropositive patients, sera from 19 of 34 (56%) patients reacted with a single antigen, whereas 11 of 34 patients (32%) had antibodies that reacted with 2 of these antigens, and 4 of 34 patients (12%) had antibodies that reacted with 3 or more of these antigens. Examples of antibody reactivity to NY-ESO-1, p53, and NY-CO-94/Seb4B are shown in Fig. 2A
. Forty patients lacked detectable high titer antibodies against these 13 antigens, although they did have serum reactivity to naturally occurring autoantigens such as NY-CO-8 and PINCH (Fig. 2B)
. The frequency of IgG antibody responses in colon cancer patients to individual antigens within this panel are shown in Table 2
. These frequencies ranged from 11 of 74 (15%) seropositivity to the p53 tumor suppressor protein to 2 of 74 (2.7%) seropositivity to SSX2, NY-CO-9/HDAC5, and NY-CO-41/MBD2.
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Tissue Expression Levels of mRNA Transcripts Encoding Antigens Associated with a Cancer-related Serological Response.
With the exception of p53 and CT antigens (NY-ESO-1, MAGE-3, and SSX2) where mutation and aberrant expression likely form the basis for immunogenicity, possible reasons underlying the immunogenicity of the remaining 9 antigens associated with a colon cancer-related serological response (NY-CO-9, NY-CO-41, NY-CO-42, NY-CO-45, NY-CO-58, NY-CO-61, NY-CO-94, NY-CO-95, and NY-REN-32) are unknown. Because immunogenicity may be related to altered expression levels in cancer, real time quantitative RT-PCR was used to measure the mRNA expression levels of these 9 antigens in a panel of 9 colon cancer specimens relative to a set of 8 normal colon tissue samples. Altered mRNA expression was defined as 3-fold differences in the expression level in colon cancer relative to normal colon, occurring in 2 or more tumor samples. As shown in Table 3
, the mRNA expression levels of 5 antigens, NY-CO-9/HDAC5, NY-CO-45, NY-CO-58/KNSL6, NY-CO-94/Seb4D, and NY-CO-95/KIAA1416, were altered. No major differences in the mRNA expression levels of the remaining 4 antigens, NY-REN-32/LMNA, NY-CO-41/MBD2, NY-CO-42/TRIP4, and NY-CO-61/HIP1R, were detected in colon cancer.
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15 and 29 times the level detected in normal colon tissue. More significantly, one of the two other up-regulated gene products, NY-CO-58/KNSL6, was overexpressed in 9 of 9 cases of colon cancer. In these patients, the mRNA expression level of NY-CO-58/KNSL6 ranged from 5 to 44 times the level detected in normal colon. The remaining antigen with up-regulated mRNA expression, NY-CO-95/KIAA1416, was overexpressed in 3 of 9 colon cancer specimens at levels ranging from 3 to 6 times greater than normal colon.
To investigate the expression level of NY-CO-58/KNSL6 and NY-CO-95/KIAA1416 in normal tissues, real-time quantitative RT-PCR was performed using a cDNA panel derived from 16 normal adult tissues. As shown in Fig. 3A
, NY-CO-58/KNSL6 mRNA was expressed in normal testis (1.15 fg) with only trace levels of mRNA detected in other normal tissues (ranging from 0.01 to 0.05 fg). In all colon tumor samples analyzed (Table 3)
, the expression levels of NY-CO-58/KNSL6 mRNA were >8 times (ranging from 0.16 to 1.5 fg) the average expression level of normal tissues (0.02 fg), excluding testis. In the case of NY-CO-95/KIAA1416 (Fig. 3B)
, transcripts were detected at moderate to high levels in 11 of 16 normal tissues, ranging from 8.09 fg to 98.4 fg. This range of expression levels was comparable with the levels detected in the 3 colon cancer specimens overexpressing NY-CO-95/KIAA1416.
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The SEREX-defined breast cancer antigen NY-BR-62/hKLP2 is a kinesin-like protein having 32% amino acid identity with NY-CO-58/KNSL6 (12)
. NY-BR-62/hKLP2 has been shown to interact functionally with the Ki-67 cell proliferation marker and may be involved in mitotic chromosome segregation (29)
. With regard to immunogenicity, NY-BR-62/hKLP2 was associated with a breast cancer-related humoral immune response but was not reactive with sera from colon cancer patients (12)
. In relation to its mRNA expression level in colon cancer, NY-BR-62/hKLP2 was found to be overexpressed in 9 of 9 cases of colon cancer, ranging from 3.5 to 28 times higher in colon cancer compared with normal colon tissue (Table 3)
. As shown in Fig. 3C
, NY-BR-62/hKLP2 is highly expressed in testis (equivalent to 270 fg of cDNA starting material), moderately expressed in thymus (89 fg), and expressed at a low to trace levels in the other 14 normal tissues (ranging from 0.32 fg to 20.2 fg). In all colon cancer samples analyzed (Table 3)
, the expression levels of NY-BR-62/hKLP2 were >23 times (ranging from 71.4 to 570 fg) the average expression level of 14 normal tissues (3.08 fg), excluding testis and thymus. Thus, two kinesin-like proteins, NY-CO-58/KNSL6 and NY-BR-62/hKLP2, believed to be associated with mitotic centromeres (30
, 31)
are overexpressed in cancer and immunogenic in cancer patients.
The NY-CO-92/SMARCA6 antigen identified in the present SEREX analysis of colon cancer is 31% identical to NY-CO-95/KIAA1416. Both NY-CO-92/SMARCA6 and NY-CO-95/KIAA1416 are members of the SNF2 family of helicases involved in chromatin remodeling, DNA repair, and DNA transcription (30
, 32)
. With regard to immunogenicity, NY-CO-92/SMARCA6 reacted with 1 of 74 serum samples from colon cancer patients. In this study, NY-CO-92/SMARCA6 transcripts were found to be overexpressed in 8 of 9 colon cancer specimens, ranging from 4.9 to 11 times higher in colon cancer compared with normal colon (Table 3)
. As shown in Fig. 3D
, NY-CO-92/SMARCA6 mRNA is ubiquitously expressed at variable levels in normal tissues with the highest levels detected in testis (equivalent to 1.8 fg of cDNA starting material), pancreas (1.0 fg), and placenta (0.95 fg). In comparison to normal tissues, the levels of NY-CO-92/SMARCA6 mRNA expression in colon cancer ranged from 2.6 to 6.3 times (1.2 to 2.9 fg) the average level detected in 16 normal tissues (0.46 fg). Thus, two members of the SNF2 family of chromatin remodeling helicases are overexpressed in colon cancer and immunogenic in colon cancer patients (30
, 32) .
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The diagnostic potential of these findings can be seen from the fact 34 of 74 serum samples (46%) from colon cancer patients detect 1 or more of the 13 antigens associated with a colon cancer-related serological response, whereas serum samples from 75 normal blood donors are not reactive with this subset of antigens. With regard to the antibody frequency toward individual antigens, an antibody response to p53 was detected in 15% of the patients, whereas the frequency of serological responses to the other 12 antigens was lower, ranging from 3 to 8% of colon cancer patients. Thus, with the exception of p53, no other serodominant antigen was defined in colon cancer, suggesting that antigen panels, rather than individual antigens, would be the best approach to developing diagnostic/monitoring methods for detecting colon cancer. This low frequency of cancer-related antibody responses in colon cancer differs from the high frequency of such responses reported for other tumors such as the antibody response to annexin I/II in 60% of lung cancer patients (33) and to PHF-3 in 60% of glioblastoma multiforme patients (10) . In our initial SEREX analysis of colon cancer (7) , 6 antigens (NY-CO-8, NY-CO-9, NY-CO-13, NY-CO-16, NY-CO-20 and NY-CO-38) were found to be associated with a cancer-related serological response, reacting with 20 of the 29 serum samples from colon cancer patients (69%) and not with sera from 15 normal individuals. These 6 antigens were incorporated into the antigen panel screened in this study, and only 2 of the antigens, NY-CO-9/HDAC5 and NY-CO-13/p53, maintained their serological association with cancer when larger numbers of normal sera (n = 75) were screened. These results point out the need to analyze large panels of sera from normal individuals and individuals with nonneoplastic conditions before claims of cancer-specific immunogenicity can be made.
The relationship between disease stage and the presence of serum IgG antibody to the panel of 13 antigens was also investigated. Seventy-one percent of stage I colon cancer patients, 36% of stage II patients, and 14% of stage III patients were found to develop a humoral immune response to 1 or more of the 13 antigens associated with a colon cancer-related serological response. This decline in seroreactivity may be a result of antigen loss, whereas the subsequent increase in seroreactivity observed in stage IV patients (52% seropositivity) may be an indication of changes in the antigenic phenotype of metastatic tumor cells or reflect a higher tumor burden, which increases the mass of antigen to levels that induce an immune response. Although some antigens appeared to be associated with serological responses at a particular disease stage (e.g., anti-NY-CO-41/MBD2 in stage I), the validity of these findings need to be confirmed using a larger series of patients. Of interest, however, was the finding that antibodies to p53 were found at all disease stages, suggesting a lack of prognostic significance in colon cancer.
In conformity with previous results (12 , 15 , 16) , a subset of the antigens associated with a colon cancer-related serological response showed aberrant mRNA expression in colon cancer. With regard to CT antigens (MAGEA3, NY-ESO-1, and SSX2), it is of interest that a previous immunohistochemical analysis showed a low frequency of CT antigen expression in colon cancer (21) , whereas our detection of antibody against these antigens suggests that these CT antigens were expressed at a significant level in some cases of colon cancer. Also, 5 of the antigens associated with a colon cancer-related serological response showed altered levels of mRNA expression, including three gene products, NY-CO-9/HDAC5, NY-CO-45, and NY-CO-94/Seb4B, which had a lower level of mRNA expression in colon cancer relative to normal colon tissue. These and previous findings (12) have raised the possibility that diminished expression, as well as heightened expression of a gene product could represent an immunogenic stimulus. Hypotheses regarding the underlying reasons for the immunogenicity of down-regulated gene products can be postulated. For example, enzymes involved in posttranslational modifications may be inactive at low substrate concentrations, producing proteins that lack certain processing signals required for the generation of a normal set of MHC-binding peptides. The end result could be the generation of a different set of MHC-binding peptides for the down-regulated gene product, which in turn induces an immune response. The SEREX-defined "3p" antigens, NY-LU-12 (34) , NY-REN-9/LUCA-15 (8) , NY-REN-10/gene21 (8) , and NY-BR-79/tata modulatory factor-1 (12) , which map to the putative tumor suppressor gene locus on 3p21 (35, 36, 37) , represent other examples of immune responses to gene products that are deleted or down-regulated in cancer. Furthermore, down-regulated expression could have etiologic implications. For example, down-regulated expression of NY-CO-9/HDAC5, a transcriptional repressor, could lead to activation of genes under its control such as MEF-2-dependent genes which regulate cell differentiation (38) .
Two of the antigens associated with a colon cancer-related serological response, NY-CO-58/KNSL6 and NY-CO-95/KIAA1416, were consistently overexpressed in colon cancer. Both NY-CO-95/KIAA1416 and a structurally related protein, NY-CO-92/SMARCA6, were overexpressed in 3 of 9 and 8 of 9 cases of colon cancer, respectively. Both proteins are members of the SNF2 family of chromatin remodeling helicases involved in DNA repair and the regulation of transcription (32)
, raising the possibility that their overexpression in cancer could be of etiological significance. NY-CO-58/KNSL6 was found to be over-expressed in the 9 colon cancer specimens examined, ranging from 5 to 44 times the level detected in normal colon tissue. NY-CO-58/KNSL6 expression in normal tissues was extremely limited, characterized by high-level mRNA expression in testis and trace level mRNA expression (
4% of the level detected in testis) in 15 other normal tissues. The immunogenicity and expression profile of NY-CO-58/KNSL6 indicate that this antigen may be an attractive cancer vaccine target, and it will be important to analyze the CD8+ and CD4+ T-cell responses to NY-CO-58/KNSL6. NY-CO-58/KNSL6 is a member of the kinesin family of motor proteins, and in particular, may be involved in chromosome segregation during mitosis (31)
. A structurally and functionally related breast cancer antigen (12)
, NY-BR-62/hKLP2 (29)
, was also shown to be overexpressed in all 9 cases of colon cancer examined with limited expression in normal tissues. It also should be evaluated with respect to its ability to induce a cellular immune response. It should be noted that bulk tumor and normal tissue were used in these studies, and therefore, the precise cell type responsible for overexpression is unclear. This will be clarified in the future by an immunohistochemical analysis of NY-CO-58/KNSL6 and NY-BR-62/hKLP2 protein expression using a set of monoclonal antibodies, currently under development.
In total, the mRNA expression profile of 8 of the 13 antigens in our panel was altered in colon cancer and this is likely the basis for their immunogenicity in colon cancer patients (3 , 6 , 12 , 14) . Additional studies are needed to verify the role of altered expression levels in inducing humoral immunity such as testing serum reactivity and mRNA expression levels in matched pairs of autologous serum and tumor specimens. Another antigen, p53, is frequently mutated in colon cancer. The underlying reasons for the immunogenicity of the remaining 4 antigens are not known. Although mutations have rarely been identified in the coding regions of SEREX-defined antigens (7) , mutational events may in fact be a major immunogenic stimulus for initiating the humoral immune response to cancer. One possible explanation for this infrequent detection of mutations is that the humoral immune response elicited by a mutational event reacts with both the wild-type and mutated product, and the wild-type product is usually isolated by SEREX. Clearly, more attention needs to be given to this possibility that mutation is responsible for the immunogenicity of antigens associated with a colon cancer-related serological response.
Although current immunodiagnostic approaches to cancer stress the detection of cancer antigens in serum, the value of monitoring the humoral immune responses of patients to cancer antigens should also be further explored for its diagnostic potential. Approximately half of the colon cancer patients analyzed in this study had serum antibodies to 1 or more members of a panel of 13 antigens associated with a colon cancer-related serological response. Additional improvements in the sensitivity of this SADA-based approach awaits the identification and addition of more antigens to this screening panel in the future.
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FOOTNOTES |
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1 Supported in part by a grant from the colon cancer collaborative of the Cancer Research Institute. 
2 To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Fax: (212) 717-3100; E-mail: scanlanm{at}mskcc.org
3 The abbreviations used are: SEREX, serological analysis of recombinant cDNA expression libraries; CT, cancer/testis; SADA, serum antibody detection array; RT-PCR, reverse transcription-PCR; FAM, 6-carboxyfluorescein.
4 Internet address: http://www.licr.org/SEREX.html.
Received 12/28/01. Accepted 5/ 7/02.
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REFERENCES |
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 M. T. Spiotto, M. A. Reth, and H. Schreiber Genetic changes occurring in established tumors rapidly stimulate new antibody responses PNAS, April 29, 2003; 100(9): 5425 - 5430. [Abstract] [Full Text] [PDF]
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S. Milutinovic, Q. Zhuang, A. Niveleau, and M. Szyf Epigenomic Stress Response. KNOCKDOWN OF DNA METHYLTRANSFERASE 1 TRIGGERS AN INTRA-S-PHASE ARREST OF DNA REPLICATION AND INDUCTION OF STRESS RESPONSE GENES J. Biol. Chem., April 18, 2003; 278(17): 14985 - 14995. [Abstract] [Full Text] [PDF]
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S.-Y. Lee, Y. Obata, M. Yoshida, E. Stockert, B. Williamson, A. A. Jungbluth, Y.-T. Chen, L. J. Old, and M. J. Scanlan Immunomic analysis of human sarcoma PNAS, March 4, 2003; 100(5): 2651 - 2656. [Abstract] [Full Text] [PDF]
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 J.-Y. Zhang, C. A. Casiano, X.-X. Peng, J. A. Koziol, E. K. L. Chan, and E. M. Tan Enhancement of Antibody Detection in Cancer Using Panel of Recombinant Tumor-associated Antigens Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 136 - 143. [Abstract] [Full Text] [PDF]
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