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REVIEW ARTICLE
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Autoantibodies in the diagnosis, prognosis, and prediction of colorectal cancer


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 Submission24-Jan-2019
Date of Decision23-Aug-2019
Date of Acceptance11-Sep-2019
Date of Web Publication09-Jun-2020

Correspondence Address:
Roshan Niloofa,
Department of Zoology and Environmental Sciences, Faculty of Science, University of Colombo, Colombo
Sri Lanka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_64_19

 > Abstract 


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



How to cite this URL:
Niloofa R, De Zoysa M I, Seneviratne L S. Autoantibodies in the diagnosis, prognosis, and prediction of colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 23]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=286252




 > Introduction Top


Colorectal cancer (CRC) is the second-most commonly diagnosed cancer worldwide.[1] 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.[2],[3] 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 Top


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.
Figure 1: Flow diagram of the literature search process for the review

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 > Autoantibodies Against Individual Tumor-Associated Antigen Top


[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.[17],[19],[27] 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.[23] 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.[4],[7],[8],[11],[12] A small number of single autoantibodies against CCD83, CEA, MAPKAPK3, PUF60, RPH 3AL, SEC61b, and SPAG9 had both a sensitivity and specificity above 70%.[5],[9],[18],[20],[41],[43],[44]
Table 1: Diagnostic performances of colorectal cancer-associated autoantibodies

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 > Autoantibodies Against A Combination Of Tumor-Associated Antigen Top


[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.[57] 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

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Another study assessed six autoantibodies against phage–peptide antigens and found good diagnostic performance (sensitivity 83.3% and specificity of 87.5%).[55] The diagnostic performance further increased when CEA was tested with the six autoantibodies (sensitivity 91.7% and specificity 95%).[55] 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%.[7] When three autoantibodies (PIM1, MAPKAPK3, and ACVR2B) were screened simultaneously by protein microarray, the sensitivity was 84% and specificity was 71%.[5]

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%.[17] 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%.[52] 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.[45] 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%.[59] 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.[57] A few studies used CEA in addition to the combinations of autoantibodies.[55],[56],[58],[60] 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 Top


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.[77] 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.[54],[70] Pedersen et al. studied the diagnostic performance of 18 epitopes of the p53 protein.[74] 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

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 > Autoantibody Levels At Different Stages Of Colorectal Cancer Top


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.[44] A combination of autoantibodies against PIM1, MAPKAPK3, and ACVR2B helps detect adenomatous polyps and predict CRC.[7] However, some studies found no difference in the presence or quantity of autoantibodies based on the clinical stage.[62],[72] 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.[67] Some studies have shown autoantibodies to be correlated with the prognosis.[70] Shiota et al. and Abe et al. have shown that higher titers of anti-p53 autoantibodies are found to have a worse prognosis.[65],[78] 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

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Table 4: Diagnostic performances of the autoantibodies according to colorectal cancer stage

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 > Conclusion Top


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.[79] In this article, we have reviewed 122 autoantibodies in 74 studies.
Table 5: Characteristics of selected tumor-associated antigens

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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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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