|Ahead of print publication
Autoantibodies in the diagnosis, prognosis, and prediction of colorectal cancer
Roshan Niloofa1, M Ishan De Zoysa2, L Suranjith Seneviratne1
1 Department of Zoology and Environmental Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka
2 Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
|Date of Submission||24-Jan-2019|
|Date of Decision||23-Aug-2019|
|Date of Acceptance||11-Sep-2019|
|Date of Web Publication||09-Jun-2020|
Department of Zoology and Environmental Sciences, Faculty of Science, University of Colombo, Colombo
Source of Support: None, Conflict of Interest: None
Colorectal cancer (CRC) is the second-most commonly diagnosed cancer worldwide. Early diagnosis improves prognosis and long-term outcomes. Several studies have found tumor-associated autoantibodies in CRC patients. We aimed to provide an overview on CRC-associated autoantibodies and their reported diagnostic, prognostic, and predictive performance when used singly or in combination. We systematically reviewed studies on CRC-related autoantibodies published till March 2018 and critically analyzed the role of these autoantibodies in CRC. In general, autoantibodies were of low sensitivity when tested individually and the diagnostic characteristics improved when tested in combination. Autoantibodies against CCD83, carcinoembryonic antigen, MAPKAPK3, RPH 3AL, SEC61b, and SPAG9 showed high sensitivity and specificity when tested alone. When tested in combination, autoantibodies against three antigens (PIM1, MAPKAPK3, and ACVR2B) showed high sensitivity and specificity. So far, most CRC-associated autoantibodies have been evaluated in single or in a small number of studies. In contrast, anti-p53 antibodies have been studied in a larger number of CRC studies, but, so far, none of them have high diagnostic characteristics. CRC-associated autoantibodies are detectable from the early stages of malignancy, pointing to their possible use in the early detection of CRC. Some studies suggest that CRC-associated autoantibodies may be a guide to prognosis in CRC.
Keywords: Anti-p53, autoantibodies, colorectal cancer, early detection, prognosis, tumor-associated antigen
| > Introduction|| |
Colorectal cancer (CRC) is the second-most commonly diagnosed cancer worldwide. Its development takes many years, and early diagnosis improves overall survival. CRC develops over a long period of time. Mutations in the antigen-presenting cells and BRAF genes produce localized polyps which then protrude toward the intestinal lumen. With time, these polyps accumulate mutations and start invading the bowel wall. As the mutated cell proliferates and the polyp size increases, further genetic mutations (such as KRAS and p53) and epigenetic alterations occur. Approximately 30% of all CRCs are inherited. Hereditary and familial CRCs such as Lynch syndrome and familial adenomatous polyposis represent around 5% of CRC cases. The exact etiology of the remaining 25% of inherited CRCs still needs to be delineated. CRC may be caused by chromosomal or microsatellite instability (MSI). Based on the microsatellite status, CRC may either be microsatellite stable (MSS) or MSI. MSI types of CRC show a higher mutation rate when compared to MSS types, and thus lead to a higher number of tumor neoantigens. These tumor-associated antigens (TAAs) may in turn stimulate the immune system to produce an antibody and cellular immune response. Plasma cells produce antibodies against the tumor neoantigens, and these tumor-associated autoantibodies may play a role in effective antitumor responses.
The outcome of CRC depends on the stage at diagnosis. Early diagnosis is important as the 5-year survival rate drops off markedly with advanced stages of disease. At the present time, CRC remains a major cause of morbidity and mortality as most cases are diagnosed at an advanced stage, especially in countries that do not have a CRC screening program. This may partly be because some of the screening techniques such as colonoscopy or sigmoidoscopy are relatively invasive. Thus, simple-to-perform, noninvasive, and good screening tests would be very helpful. The presently established noninvasive guaiac fecal occult blood test has a low sensitivity., A blood-based test would be easier to do when screening large populations. Some TAAs may be used as biomarkers, but their diagnostic accuracy is too lower for use in clinical practice. Autoantibodies produced against TAAs can be detected in blood. Antibodies are more stable than antigens, as their degradation is much less. Therefore, detection of autoantibodies might be a promising diagnostic tool in CRC. It may help with detection of early stages of disease. We have reviewed the published studies on CRC-associated autoantibodies and outlined their reported diagnostic performance when used singly or in combination.
| > Literature Search|| |
A systemic literature search was performed to identify studies evaluating autoantibodies for the early detection and prognosis of CRC. Articles until March 2018 were searched in PubMed and EMBASE. The keywords used in the search were colorectal cancer, autoantibodies, antibody, biomarker, detection, diagnosis, and prognosis. Duplicate articles were excluded, and the initial selection was based on the title and abstract and then the full-text articles were read. Studies on humans and in English were considered. Studies that did not have noncancer controls and those using biomarkers other than autoantibodies were excluded. Furthermore, the studies that did not provide measures of diagnostic performance such as sensitivity or specificity or where it was not possible to calculate them from the data provided were also excluded. [Figure 1] outlines the search strategy for the selection of publications for this review. A total of 430 articles were found and after removal of 112 duplicate articles, the title and abstracts of the others were reviewed. Potentially relevant articles (n = 107) were reviewed by reading the full text. Thirty-five articles were excluded for the following reasons: nonhuman studies (n = 7), articles are not in English (n = 6), lack of information on diagnostic performance (n = 16), and those that did not include controls (n = 6). Finally, 72 studies (number of patients = 8764) were included in this review.
| > Autoantibodies Against Individual Tumor-Associated Antigen|| |
[Table 1] summarizes the diagnostic performance of the autoantibodies when studied individually. Overall, autoantibodies against 79 TAAs were studied in 48 studies (number of patients = 4403). Most studies were done using small number of samples (i.e., <100). Serum autoantibodies against some TAAs such as p53, p62, carcinoembryonic antigen (CEA), c-myc, and Ras have been detected in CRC patients.,, The autoantibody profile against the cell adhesion molecule GA733-2 was studied in 1068 CRC patients. Although specificity was 100%, sensitivity was low at 15% and the number of controls included was small. High specificities (>85%) and low sensitivities (<30%) were seen for autoantibodies against many TAAs (number of autoantibodies = 69, 59.5%) such as ACTR1A, AFP, Annexin, BCP20, and Calnuc.,,,, A small number of single autoantibodies against CCD83, CEA, MAPKAPK3, PUF60, RPH 3AL, SEC61b, and SPAG9 had both a sensitivity and specificity above 70%.,,,,,,
|Table 1: Diagnostic performances of colorectal cancer-associated autoantibodies|
Click here to view
| > Autoantibodies Against A Combination Of Tumor-Associated Antigen|| |
[Table 2] summarizes the diagnostic performance of combinations of CRC-associated autoantibodies. There were 22 studies that included 2287 CRC patients. There is an increase in diagnostic performance when combinations of autoantibodies are used. In 2011, Chang et al. found five phage–peptides to be promising for differentiating CRC patients from healthy controls. The diagnostic performance was high (90% sensitivity and 91.7% specificity), and two novel peptides (i.e., no homology with any other known proteins) were noted. However, the sample size was small (n = 60), and the assay was not able to discriminate CRC from autoimmune diseases. The five phage–peptides were not studied individually to enable the identification of the most immune-reactive antigen.
|Table 2: Diagnostic performance of the autoantibodies against different combinations of colorectal cancer tumor-associated antigens|
Click here to view
Another study assessed six autoantibodies against phage–peptide antigens and found good diagnostic performance (sensitivity 83.3% and specificity of 87.5%). The diagnostic performance further increased when CEA was tested with the six autoantibodies (sensitivity 91.7% and specificity 95%). Four of these peptides were not found in known human protein sequences. In a study that tested autoantibodies against 32 TAAs, positive responses were seen against six TAAs which had a sensitivity of 61.1% and a specificity of 80.9%. When three autoantibodies (PIM1, MAPKAPK3, and ACVR2B) were screened simultaneously by protein microarray, the sensitivity was 84% and specificity was 71%.
Although some autoantibodies had low diagnostic performance when studied individually, they showed an increase in sensitivity when studied in combination. For example, when five autoantibodies were studied individually, between 18.1% and 35.1% were found to be positive, whereas in combination, this increased to 58.5%. Similarly, when O'Reilly et al. studied autoantibodies against zinc finger factors, sensitivities ranged from 10% to 20%, but when assessed in combination, this increased to 42%. However, in both these studies, although sensitivity increased, it was still insufficient for use in clinical practice. When anti-survivin autoantibodies and CEA were studied together, specificity increased from 64% to 90% although sensitivity was slightly decreased. Chen et al. assessed the sensitivity and specificity of nine autoantibodies and found anti-MAGE4 to have a low sensitivity of 11% and a specificity of 96%, and anti-p53 was able to detect only 8% of CRC patients although specificity was 100%. Sensitivity increased when the autoantibodies were analyzed in combination. For example, when autoantibodies against p53, IMPDH2, MDM2, MAGEA4, CTAG1, and MTDH were tested together, sensitivity was 40% and specificity was 88%. Chang et al. showed that the diagnostic performance of autoantibodies against 5-phage peptides was significantly higher in colorectal polyp patients than that in healthy controls. A few studies used CEA in addition to the combinations of autoantibodies.,,, These studies showed mixed results as some improved performance and others did not. Therefore, it would be important to carefully select appropriate combinations of TAA for achieving best performance characteristics.
| > Autoantibodies Against P53|| |
Twenty-eight studies (with 4763 patients) have assessed the use of anti-p53 autoantibodies for the diagnosis of CRC. The diagnostic performance observed in these studies is shown in [Table 3]. Most of the studies had small sample sizes. When tested individually, sensitivity for the diagnosis of CRC ranged from 4% to 63% and specificity was higher at 89%–100%. Houbiers et al. found the presence of p53 antiantibodies to be correlated with a reduced survival rate. In the 249 CRC patients studied, the presence of anti-p53 antibodies correlated with prognostic factors such as histological differentiation grade, shape of tumor, and tumor invasion into blood vessels. Those with p53 autoantibodies had a reduced disease-free survival rate and autoantibody titers decreased during treatment. However, some other studies have found no correlation between anti-p53 antibodies and CRC prognosis., Pedersen et al. studied the diagnostic performance of 18 epitopes of the p53 protein. They failed to identify an epitope that produced high sensitivity (the highest sensitivity was 24%).
|Table 3: Diagnostic performances of the autoantibodies against p53 in colorectal cancer|
Click here to view
| > Autoantibody Levels At Different Stages Of Colorectal Cancer|| |
CRC may be cured if diagnosed early, thus highlighting the importance of predicting CRC before the onset of clinical symptoms. [Figure 2] illustrates the process of autoantibody formation against TAA at different stages of cancer. The diagnostic performance of autoantibodies according to CRC stage has been assessed in twenty studies (number of patients = 5271), and their findings are shown in [Table 4]. Most studies did not show clear differences in diagnostic performance between the early and late stages of CRC. In addition, Kanojia et al. found anti-SPAG9 antibodies to have higher sensitivity in the early (I and II) compared to the late (III and IV) stages. A combination of autoantibodies against PIM1, MAPKAPK3, and ACVR2B helps detect adenomatous polyps and predict CRC. However, some studies found no difference in the presence or quantity of autoantibodies based on the clinical stage., Overall, these findings point to the possibility of using these biomarkers for detecting CRC at an early stage. Most of the studies have employed small number of patients at each CRC stage. Tang et al. studied a larger number of patients at CRC stages II to IV and found sensitivity to be low (<20%) at each stage. Some studies have shown autoantibodies to be correlated with the prognosis. Shiota et al. and Abe et al. have shown that higher titers of anti-p53 autoantibodies are found to have a worse prognosis., It has been hypothesized that as the disease advances, tumor mutation rate and the presence of TAAs increase. This, in turn, stimulates the humoral immune response to produce higher autoantibody levels. The higher quantity of autoantibodies may lead to increased inflammation and thus contribute to disease progression.
|Figure 2: Immune recognition and response to tumor cell. Tumor-associated antigens are either presented by antigen-presenting cells to immune cells or the immune cells may respond directly to the tumor antigens. Immune cells would then recognize these new tumor-associated antigens and produce autoantibodies against them|
Click here to view
|Table 4: Diagnostic performances of the autoantibodies according to colorectal cancer stage|
Click here to view
| > Conclusion|| |
In this review, we summarized and analyzed the clinical utility of autoantibodies in the diagnosis, prognosis, and prediction of CRC. Studies done, so far, suggest that autoantibodies against CCD83, CEA, MAPKAPK3, RPH 3AL, SEC61b, and SPAG9 have high sensitivity and specificity when tested alone. Whereas when tested in combination, autoantibodies against three antigens (PIM1, MAPKAPK3, and ACVR2B) showed high sensitivity and specificity. Important characteristics of these Tumour associated antigens are outlined in [Table 5]. Although studies from 1990 to 2018 were included, half of the studies were published after 2008. The more recent studies were done using newer technologies such as SEREX, microarrays, and phage display. Previously, Chen et al. reviewed the diagnostic performances of 109 autoantibodies in 63 studies published until 2013. In this article, we have reviewed 122 autoantibodies in 74 studies.
Most individual CRC-associated autoantibodies tend to have a low sensitivity and high specificity. Diagnostic performance was better with a combination of autoantibodies and varied across studies when the same autoantibody was used individually or in similar combinations. This may have been due to differences in sample size, the process of extracting TAAs, and the methods used for testing. Seven autoantibodies showed promising diagnostic performance (sensitivity >70% and specificity >70%), but were studied in only one study each and had relatively low sample sizes (range: 37–92). Many of the autoantibodies are against TAAs that are common to different cancers. Thus, their detection may only suggest the presence of a cancer, and further studies to identify CRC-specific autoantibodies would be needed.
CRC-associated autoantibodies may be used as a promising biomarker for the early diagnosis, prognosis, and prediction of CRC. Furthermore, they may act as a guide for the selection of appropriate immune molecules for use in targeted CRC immunotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
Brenner H, Hoffmeister M, Birkner B, Stock C. Diagnostic performance of guaiac-based fecal occult blood test in routine screening: State-wide analysis from Bavaria, Germany. Am J Gastroenterol 2014;109:427-35.
Lee CS, Ronan L, O'Morain C, McNamara D. Screening for colorectal cancer: What fits best? Expert Rev Gastroenterol Hepatol 2012;6:301-12.
Kiyamova R, Garifulin O, Gryshkova V, Kostianets O, Shyian M, Gout I, et al.
Preliminary study of thyroid and colon cancers-associated antigens and their cognate autoantibodies as potential cancer biomarkers. Biomarkers 2012;17:362-71.
Babel I, Barderas R, Díaz-Uriarte R, Martínez-Torrecuadrada JL, Sánchez-Carbayo M, Casal JI. Identification of tumor-associated autoantigens for the diagnosis of colorectal cancer in serum using high density protein microarrays. Mol Cell Proteomics 2009;8:2382-95.
Chen X, Dong K, Long M, Lin F, Wang X, Wei J, et al.
Serum anti-AEG-1 auto-antibody is a potential novel biomarker for malignant tumors. Oncol Lett 2012;4:319-23.
Negm OH, Hamed MR, Schoen RE, Whelan RL, Steele RJ, Scholefield J, et al.
Human blood autoantibodies in the detection of colorectal cancer. PLoS One 2016;11:e0156971.
Song J, Sun X, Sokoll LJ, Maki M, Tian Y, Chan DW, et al
. Detection of autoantibodies to annexin A11 in different types of human cancer. Clin Proteomics 2009;5:7.
Chen JS, Chou YP, Chen KT, Hung RP, Yu JS, Chang YS, et al.
Detection of annexin A autoantibodies in sera from colorectal cancer patients. J Clin Gastroenterol 2011;45:125-32.
Jiang B, Ren T, Dong B, Qu L, Jin G, Li J, et al.
Peptide mimic isolated by autoantibody reveals human arrest defective 1 overexpression is associated with poor prognosis for colon cancer patients. Am J Pathol 2010;177:1095-103.
Song MH, Ha JC, Lee SM, Park YM, Lee SY. Identification of BCP-20 (FBXO39) as a cancer/testis antigen from colon cancer patients by SEREX. Biochem Biophys Res Commun 2011;408:195-201.
Chen Y, Lin P, Qiu S, Peng XX, Looi K, Farquhar MG, et al.
Autoantibodies to Ca2+binding protein calnuc is a potential marker in colon cancer detection. Int J Oncol 2007;30:1137-44.
Liu W, Wang P, Li Z, Xu W, Dai L, Wang K, et al.
Evaluation of tumour-associated antigen (TAA) miniarray in immunodiagnosis of colon cancer. Scand J Immunol 2009;69:57-63.
Looi K, Megliorino R, Shi FD, Peng XX, Chen Y, Zhang JY. Humoral immune response to p16, a cyclin-dependent kinase inhibitor in human malignancies. Oncol Rep 2006;16:1105-10.
Zhang JY, Casiano CA, Peng XX, Koziol JA, Chan EK, Tan EM. Enhancement of antibody detection in cancer using panel of recombinant tumor-associated antigens. Cancer Epidemiol Biomarkers Prev 2003;12:136-43.
Ben-Mahrez K, Sorokine I, Thierry D, Kawasumi T, Ishii S, Salmon R, et al.
Circulating antibodies against c-myc oncogene product in sera of colorectal cancer patients. Int J Cancer 1990;46:35-8.
Chan CC, Fan CW, Kuo YB, Chen YH, Chang PY, Chen KT, et al.
Multiple serological biomarkers for colorectal cancer detection. Int J Cancer 2010;126:1683-90.
Song MH, Ha JM, Shin DH, Lee CH, Old L, Lee SY. KP-CoT-23 (CCDC83) is a novel immunogenic cancer/testis antigen in colon cancer. Int J Oncol 2012;41:1820-6.
Wu XJ, Fang YJ, Lin JZ, Lu ZH, Li LR, Chen G, et al.
Circulating antibodies to carcinoembryonic antigen related to improved recurrence-free survival of patients with colorectal carcinoma. J Int Med Res 2011;39:838-45.
Albanopoulos K, Armakolas A, Konstadoulakis MM, Leandros E, Tsiompanou E, Katsaragakis S, et al.
Prognostic significance of circulating antibodies against carcinoembryonic antigen (anti-CEA) in patients with colon cancer. Am J Gastroenterol 2000;95:1056-61.
Konstadoulakis MM, Syrigos KN, Albanopoulos C, Mayers G, Golematis B. The presence of anti-carcinoembryonic antigen (CEA) antibodies in the sera of patients with gastrointestinal malignancies. J Clin Immunol 1994;14:310-3.
Xia Q, Kong XT, Zhang GA, Hou XJ, Qiang H, Zhong RQ. Proteomics-based identification of DEAD-box protein 48 as a novel autoantigen, a prospective serum marker for pancreatic cancer. Biochem Biophys Res Commun 2005;330:526-32.
Mosolits S, Harmenberg U, Rudén U, Ohman L, Nilsson B, Wahren B, et al.
Autoantibodies against the tumour-associated antigen GA733-2 in patients with colorectal carcinoma. Cancer Immunol Immunother 1999;47:315-20.
Babel I, Barderas R, Diaz-Uriarte R, Moreno V, Suarez A, Fernandez-Aceñero MJ, et al.
Identification of MST1/STK4 and SULF1 proteins as autoantibody targets for the diagnosis of colorectal cancer by using phage microarrays. Mol Cell Proteomics 2011;10:M110.001784.
Tsunemi S, Nakanishi T, Fujita Y, Bouras G, Miyamoto Y, Miyamoto A, et al.
Proteomics-based identification of a tumor-associated antigen and its corresponding autoantibody in gastric cancer. Oncol Rep 2010;23:949-56.
Shebzukhov YV, Koroleva EP, Khlgatian SV, Belousov PV, Kuz'mina KE, Radko BV, et al.
Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients. Int J Cancer 2005;117:800-6.
Scanlan MJ, Welt S, Gordon CM, Chen YT, Gure AO, Stockert E, et al.
Cancer-related serological recognition of human colon cancer: Identification of potential diagnostic and immunotherapeutic targets. Cancer Res 2002;62:4041-7.
Kamei M, Kato M, Mochizuki K, Kuroda K, Sato S, Hashizume S, et al.
Serodiagnosis of cancers by ELISA of anti-histone H2B antibody. Biotherapy 1992;4:17-22.
He Y, Wu Y, Mou Z, Li W, Zou L, Fu T, et al.
Proteomics-based identification of HSP60 as a tumor-associated antigen in colorectal cancer. Proteomics Clin Appl 2007;1:336-42.
Fujita Y, Nakanishi T, Miyamoto Y, Hiramatsu M, Mabuchi H, Miyamoto A, et al.
Proteomics-based identification of autoantibody against heat shock protein 70 as a diagnostic marker in esophageal squamous cell carcinoma. Cancer Lett 2008;263:280-90.
Li Y, Jiang T, Zhang J, Zhang B, Yang W, You G, et al.
Elevated serum antibodies against insulin-like growth factor-binding protein-2 allow detecting early-stage cancers: Evidences from glioma and colorectal carcinoma studies. Ann Oncol 2012;23:2415-22.
He Y, Mou Z, Li W, Liu B, Fu T, Zhao S, et al.
Identification of IMPDH2 as a tumor-associated antigen in colorectal cancer using immunoproteomics analysis. Int J Colorectal Dis 2009;24:1271-9.
Zhang JY, Chan EK, Peng XX, Lu M, Wang X, Mueller F, et al.
Autoimmune responses to mRNA binding proteins p62 and Koc in diverse malignancies. Clin Immunol 2001;100:149-56.
Xu QW, Zhao W, Wang Y, Sartor MA, Han DM, Deng J, et al.
An integrated genome-wide approach to discover tumor-specific antigens as potential immunologic and clinical targets in cancer. Cancer Res 2012;72:6351-61.
Silk AW, Schoen RE, Potter DM, Finn OJ. Humoral immune response to abnormal MUC1 in subjects with colorectal adenoma and cancer. Mol Immunol 2009;47:52-6.
Nakamura H, Hinoda Y, Nakagawa N, Makiguchi Y, Itoh F, Endo T, et al.
Detection of circulating anti-MUC1 mucin core protein antibodies in patients with colorectal cancer. J Gastroenterol 1998;33:354-61.
Pedersen JW, Blixt O, Bennett EP, Tarp MA, Dar I, Mandel U, et al.
Seromic profiling of colorectal cancer patients with novel glycopeptide microarray. Int J Cancer 2011;128:1860-71.
Kocer B, McKolanis J, Soran A. Humoral immune response to MUC5AC in patients with colorectal polyps and colorectal carcinoma. BMC Gastroenterol 2006;6:4.
Liu W, Li Z, Xu W, Wang Q, Yang S. Humoral autoimmune response to IGF2 mRNA-binding protein (IMP2/p62) and its tissue-specific expression in colon cancer. Scand J Immunol 2013;77:255-60.
Kobayashi S, Hoshino T, Hiwasa T, Satoh M, Rahmutulla B, Tsuchida S, et al.
Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients. Oncotarget 2016;7:82493-503.
Takahashi M, Chen W, Byrd DR, Disis ML, Huseby ES, Qin H, et al.
Antibody to ras proteins in patients with colon cancer. Clin Cancer Res 1995;1:1071-7.
Chen JS, Kuo YB, Chou YP, Chan CC, Fan CW, Chen KT, et al.
Detection of autoantibodies against rabphilin-3A-like protein as a potential biomarker in patient's sera of colorectal cancer. Clin Chim Acta 2011b;412:1417-22.
Fan CW, Chan CC, Chen KT, Twu J, Huang YS, Han CL, et al.
Identification of SEC61β and its autoantibody as biomarkers for colorectal cancer. Clin Chim Acta 2011;412:887-93.
Kanojia D, Garg M, Gupta S, Gupta A, Suri A. Sperm-associated antigen 9 is a novel biomarker for colorectal cancer and is involved in tumor growth and tumorigenicity. Am J Pathol 2011;178:1009-20.
Chen JS, Chen KT, Fan WC, Yu JS, Chang YS, Chan EC. Combined analysis of survivin autoantibody and carcinoembryonic antigen biomarkers for improved detection of colorectal cancer. Clin Chem Lab Med 2010;48:719-25.
Rohayem J, Diestelkoetter P, Weigle B, Oehmichen A, Schmitz M, Mehlhorn J, et al.
Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients. Cancer Res 2000;60:1815-7.
Megliorino R, Shi FD, Peng XX, Wang X, Chan EK, Tan EM, et al.
Autoimmune response to anti-apoptotic protein survivin and its association with antibodies to p53 and c-myc in cancer detection. Cancer Detect Prev 2005;29:241-8.
Hanafusa T, Mohamed AE, Domae S, Nakayama E, Ono T. Serological identification of Tektin5 as a cancer/testis antigen and its immunogenicity. BMC Cancer 2012;12:520.
Syrigos KN, Charalampopoulos A, Pliarchopoulou K, Syrigou EI, Avuzuklidou M, Manouras A, et al.
Prognostic significance of autoantibodies against tropomyosin in patients with colorectal adenocarcinoma. Hybridoma 1999;18:543-6.
Nam MJ, Madoz-Gurpide J, Wang H, Lescure P, Schmalbach CE, Zhao R, et al.
Molecular profiling of the immune response in colon cancer using protein microarrays: Occurrence of autoantibodies to ubiquitin C-terminal hydrolase L3. Proteomics 2003;3:2108-15.
Rimm DL, Holland TE, Morrow JS, Anderson JM. Autoantibodies specific for villin found in patients with colon cancer and other colitides. Dig Dis Sci 1995;40:389-95.
O'Reilly JA, Fitzgerald J, Fitzgerald S, Kenny D, Kay EW, O'Kennedy R, et al.
Diagnostic potential of zinc finger protein-specific autoantibodies and associated linear B-cell epitopes in colorectal cancer. PLoS One 2015;10:e0123469.
Koziol JA, Zhang JY, Casiano CA, Peng XX, Shi FD, Feng AC, et al.
Recursive partitioning as an approach to selection of immune markers for tumor diagnosis. Clin Cancer Res 2003;9:5120-6.
Müller M, Meyer M, Schilling T, Ulsperger E, Lehnert T, Zentgraf H, et al.
Testing for anti-p53 antibodies increases the diagnostic sensitivity of conventional tumor markers. Int J Oncol 2006;29:973-80.
Ran Y, Hu H, Zhou Z, Yu L, Sun L, Pan J, et al.
Profiling tumor-associated autoantibodies for the detection of colon cancer. Clin Cancer Res 2008;14:2696-700.
Kojima T, Yoshikawa K, Matsui T, Kodera Y, Kojima H. Titration of serum CEA, p53 antibodies and CEA-IgM complexes in patients with colorectal cancer. Mol Med Rep 2009;2:477-80.
Chang W, Wu L, Cao F, Liu Y, Ma L, Wang M, et al.
Development of autoantibody signatures as biomarkers for early detection of colorectal carcinoma. Clin Cancer Res 2011;17:5715-24.
Kojima T, Matsui T, Fujimitsu Y, Kojima H, Uno H, Hiramatsu K, et al
. Titration of serum CEA, p53 antibodies and CEA-IgM complexes in 142 patients with colorectal cancer and 150 healthy blood donors. Ann Cancer Res 2011;19:5.
Chen H, Werner S, Butt J, Zörnig I, Knebel P, Michel A, et al.
Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting. Oncotarget 2016;7:16420-32.
Fan CW, Kuo YB, Lin GP, Chen SM, Chang SH, Li BA, et al.
Development of a multiplexed tumor-associated autoantibody-based blood test for the detection of colorectal cancer. Clin Chim Acta 2017;475:157-63.
Hammel P, Boissier B, Chaumette MT, Piedbois P, Rotman N, Kouyoumdjian JC, et al.
Detection and monitoring of serum p53 antibodies in patients with colorectal cancer. Gut 1997;40:356-61.
Angelopoulou K, Stratis M, Diamandis EP. Humoral immune response against p53 protein in patients with colorectal carcinoma. Int J Cancer 1997;70:46-51.
Hallak R, Mueller J, Lotter O, Gansauge S, Gansauge F, el-Deen Jumma M, et al.
P53 genetic alterations, protein expression and autoantibodies in human colorectal carcinoma: A comparative study. Int J Oncol 1998;12:785-91.
Bielicki D, Karbowniczek M, Sulzyc-Bielicka V, Kładny J, Boer C, Marlicz K, et al.
Clinico-pathological characteristics of colorectal cancer and serum anti-p53 antibodies. Pol J Pathol 1999;50:77-81.
Shiota G, Ishida M, Noguchi N, Oyama K, Takano Y, Okubo M, et al.
Circulating p53 antibody in patients with colorectal cancer: Relation to clinicopathologic features and survival. Dig Dis Sci 2000;45:122-8.
Takeda A, Shimada H, Nakajima K, Imaseki H, Suzuki T, Asano T, et al.
Monitoring of p53 autoantibodies after resection of colorectal cancer: Relationship to operative curability. Eur J Surg 2001;167:50-3.
Tang R, Ko MC, Wang JY, Changchien CR, Chen HH, Chen JS, et al.
Humoral response to p53 in human colorectal tumors: A prospective study of 1,209 patients. Int J Cancer 2001;94:859-63.
Broll R, Duchrow M, Oevermann E, Wellm C, Schwandner O, Schimmelpenning H, et al.
P53 autoantibodies in sera of patients with a colorectal cancer and their association to p53 protein concentration and p53 immunohistochemistry in tumor tissue. Int J Colorectal Dis 2001;16:22-7.
Shimada H, Ochiai T, Nomura F; Japan p53 Antibody Research Group. Titration of serum p53 antibodies in 1,085 patients with various types of malignant tumors: A multiinstitutional analysis by the Japan p53 Antibody Research Group. Cancer 2003;97:682-9.
Lechpammer M, Lukac J, Lechpammer S, Kovacević D, Loda M, Kusić Z. Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy. Int J Colorectal Dis 2004;19:114-20.
Chang SC, Lin JK, Lin TC, Liang WY. Genetic alteration of p53, but not overexpression of intratumoral p53 protein, or serum p53 antibody is a prognostic factor in sporadic colorectal adenocarcinoma. Int J Oncol 2005;26:65-75.
Suppiah A, Alabi A, Madden L, Hartley JE, Monson JR, Greenman J. Anti-p53 autoantibody in colorectal cancer: Prognostic significance in long-term follow-up. Int J Colorectal Dis 2008;23:595-600.
Wu J, Qiu T, Pan P, Yu D, Ju Z, Qu X, et al.
Detection of serum anti-P53 antibodies from patients with colorectal cancer in China using a combination of P53 – And phage-ELISA: Correlation to clinical parameters. Asian Pac J Cancer Prev 2011;12:2921-4.
Pedersen JW, Gentry-Maharaj A, Fourkala EO, Dawnay A, Burnell M, Zaikin A, et al.
Early detection of cancer in the general population: A blinded case-control study of p53 autoantibodies in colorectal cancer. Br J Cancer 2013;108:107-14.
Kumamoto K, Ishida H, Kuwabara K, Amano K, Chika N, Okada N, et al.
Clinical significance of serum anti-p53 antibody expression following curative surgery for colorectal cancer. Mol Clin Oncol 2017;7:595-600.
Teras LR, Gapstur SM, Maliniak ML, Jacobs EJ, Gansler T, Michel A, et al.
Prediagnostic antibodies to serum p53 and subsequent colorectal cancer. Cancer Epidemiol Biomarkers Prev 2018;27:219-23.
Houbiers JG, van der Burg SH, van de Watering LM, Tollenaar RA, Brand A, van de Velde CJ, et al.
Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br J Cancer 1995;72:637-41.
Abe S, Kawai K, Ishihara S, Nozawa H, Hata K, Kiyomatsu T, et al.
Prognostic value of pre- and postoperative anti-p53 antibody levels in colorectal cancer patients: A Retrospective study. Oncology 2017;92:31-8.
Chen H, Werner S, Tao S, Zörnig I, Brenner H. Blood autoantibodies against tumor-associated antigens as biomarkers in early detection of colorectal cancer. Cancer Lett 2014;346:178-87.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]