1Department of Internal Medicine, 3rd Fleet Medical Corps, Republic of Korea Navy, Yeongam, Korea
2Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
© Copyright 2020. Korean Association for the Study of Intestinal Diseases. All rights reserved.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
FINANCIAL SUPPORT
The authors received no financial support for the research, authorship, and/or publication of this article.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTION
Conceptualization, writing, editing: Joo YE. Conceptualization and writing: Oh HH. Approval of final manuscript: all authors.
Biomarker | Explanation |
---|---|
Tissue biomarker | |
Cytokeratins (CKs) | 65%–95% of CRC cases show a CK7–/CK20+ pattern. [10] |
Caudal type homeobox 2 (CDX2) | Sensitivity and specificity of CDX2 expression in CRC diagnosing is greater than 90%. As CDX2 expression alone cannot differentiate among adenocarcinomas of the GI tract, [13,14] it is useful as an adjunct to CKs. |
Special AT-rich sequence binding protein2 (SATB2) | The addition of SATB2 to standard panels showed no significant improvement in sensitivity or specificity in the diagnosis of CRC. [18] As SATB2 expression was positive in 95% of metastatic CRC and 0% of ovarian carcinoma cases, it could be useful as a marker to exclude ovarian carcinomas. [19,20] |
Cadherin 17 (CDH17) | Cadherins are cell–cell adhesion molecules that play important roles in maintaining tissue structure under normal conditions. [21] CDH17 is reportedly expressed in 96%–100% of primary and 100% of metastatic CRC. [25-27] |
Telomerase | Telomerase is a ribonucleoprotein that maintains telomeres by adding TTAGGG repeats onto them. [29] Cancer cells bypass DNA damage-induced inhibitory signaling pathways by upregulating telomerase. Using TBT, telomerase showed 95% sensitivity and 95% specificity in CRC. [32] |
GPA33 (A33) | A33 is expressed in the stomach, small intestine, colon, and rectal epithelial cells. It is expressed in more than 95% of human CRC. [35] Also, an immunohistological study comparing A33 and CDX2 revealed that A33 showed similar sensitivity as but a higher specificity than CDX2 as an immunomarker of CRC. [36] |
Blood biomarker | |
Circulating cell-free DNA (cfDNA) | The cfDNA is released as much larger fragments in tumor cells than in normal cells. [41] Quantitative analysis of circulating cfDNAs by measuring the ratio of longer and shorter DNA fragments, in other words, measuring cfDNA integrity number during the diagnosis of CRC, showed sensitivity of 73%–90% and specificity of 97%–85%. [42,43] |
MicroRNA (miRNA) | The miRNAs are 18–25 bp-long small noncoding RNAs that regulate gene expression by binding to mRNA. [47] Compared to mRNA, miRNAs show higher stability in the blood. Different combinations of miRNA showed high sensitivity and specificity for detecting CRC. [52,53] |
Long noncoding RNA (lncRNA) | HIF1A-AS1 showed high diagnostic ability of CRC with an AUC of 0.960. CRC patients with high HIF1A-AS1 expressions were associated with shorter 5-year survival rate than those with low HIF1A-AS1 expression. [56] |
CRNDE-h showed better diagnostic value compared to CEA. When combined with CEA, he diagnostic value improved. [57] | |
Other markers such as NEAT1, ZFAS1, and GAS5 showed promising results for potential use as a diagnostic or prognostic marker. | |
Insulin-like growth factor binding protein 2(IGFBP-2) | An elevated serum IGFBP-2 level is associated with malignancies of the colon, ovary, and prostate as well as other advanced solid tumors. [62-65] Although the sensitivity and specificity of IGFBP-2 alone is unsatisfactory for early CRC and colon polyp detection, the combination of IGFBP-2 and CEA could increase its sensitivity. [61,66] |
Stool biomarker | |
Guaiac fecal occult blood test (gFOBT) | Use of the gFOBT as a CRC screening test reduced mortality by 11%–33% over 20 years of follow-up. [67-69] However, it cannot distinguish upper GI bleeding from lower GI bleeding or human heme from non-human heme. [70] |
Fecal immunochemical test (FIT) | The FIT detects human globin using a human hemoglobin–specific immunoassay. [72] It has higher sensitivity and specificity than gFOBT for detecting CRC and advanced adenomas. [73] |
Stool DNA (sDNA) | The Cologuard test (multi-target stood DNA test for CRC) showed higher sensitivity than gFOBT and FIT but also a higher false positive rate. [86,87] |
Stool miRNA | miR-92a, miR-21, miR144, miR-106a, miR17-92 cluster, miR135 were up-regulated in CRC, while miR-143 and miR-145 were down-regulated in CRC. [92-94] However, none of the miRNAs showed adequate predictive value for use as a standalone CRC diagnostic test. |
Biomarker | Explanation |
---|---|
Tissue biomarker | |
BRAF | Comprises the mitogen-activated protein kinase pathway, which is associated with cell differentiation, migration, angiogenesis, and proliferation. [95] BRAF mutation is associated with poorer PFS and OS. [99,100] The analysis of its prognostic role is recommended. [101] |
MSI | MSI-high tumors have better prognosis than MSI-low tumors. [97,98] MSI CRC patients showed longer OS and DFS than MSS CRC patients. [110] |
CIMP | The prognostic role of CIMP is unclear. However, the majority of studies reported that CIMP+/CIMP-high CRC patients showed poorer prognosis than CIMP–/CIMP-high CRC patients. [116] |
APC | APC is associated with FAP and most cases of sporadic CRC. [109] APC mutation can cause unregulated transcription of many oncogenes. [117] Patients with APC mutation and high miR-21 reportedly had shorter OS. [118] |
p53 | Some studies reported its association with lower DFS, [103] RFS, [121] and OS [122] rates, but others reported no evidence of a prognostic role. [106,107] |
SMAD4 | SMAD4 mediates the TGF-β superfamily signaling pathway, which is frequently altered in human cancers. [125] Loss of SMAD4 was associated with poor DFS and OS. [129] |
Blood biomarker | |
CEA | CEA level is reportedly significantly associated with patient outcomes. [134] Preoperative CEA level was significantly associated with prognosis in patients with CRC metastasized to the liver. [135,136] |
NLR | Patients with elevated NLR were significantly associated with shorter OS and shorter PFS after treatment. [142] CRC patients with a pretreatment NLR < 5 were more likely to have 5-year OS and DFS. [143] Also, elevated pretreatment NLR was significantly related with poor OS and RFS in patients with liver metastasis. [144] |
cfDNA | CRC patients with higher cfDNA concentrations showed a higher risk of recurrence and shorter OS. [44,128] Detectable APC, KRAS, and p53 mutations in the serum were significantly associated with a higher rate of postoperative metastasis/recurrence. [146] |
PFS, progression-free survival; OS, overall survival; MSI, microsatellite instability; CRC, colorectal cancer; DFS, disease-free survival; MSS, microsatellite stable; CIMP, cytosine preceding guanine island methylator phenotype; FAP, familial adenomatous polyposis; RFS, relapse-free survival; TGF-β, transforming growth factor-β; NLR, neutrophil-to-lymphocyte ratio.
Biomarker | Explanation |
---|---|
Tissue biomarker | |
KRAS, NRAS | KRAS proto-oncogene encodes a GTPase protein (KRAS) that plays an essential role in many molecular pathways including the EGFR pathway. [149] Only wild-type RAS tumors showed the clinical benefit of anti-EGFR antibody therapy. KRAS mutations can be used as a negative predictive factor of a response to EGFR inhibitors. [150-153] |
BRAF | It has been reported that there is insufficient evidence that BRAF mutation could be used as a predictive marker for the benefit of anti-EGFR antibody therapy. [155] |
PIK3CA | Results are contradictory about whether PIK3CA mutation is associated with poor PFS and OS in KRAS wild-type CRC patients. [159,160] |
Blood biomarker | |
cfDNA | The cfDNA concentration decreased after primary resection, but when the CRC relapsed, cfDNA levels dramatically increased. [45,145] Similar results were found in rectal cancer patients who underwent chemoradiotherapy: The cfDNA concentration decreased in responders but increased in nonresponders. [165] |
LncRNA PTTG3P Sponge Absorbs microRNA-155-5P to Promote Metastasis of Colorectal Cancer
Biomarker | Explanation |
---|---|
Tissue biomarker | |
Cytokeratins (CKs) | 65%–95% of CRC cases show a CK7–/CK20+ pattern. [10] |
Caudal type homeobox 2 (CDX2) | Sensitivity and specificity of CDX2 expression in CRC diagnosing is greater than 90%. As CDX2 expression alone cannot differentiate among adenocarcinomas of the GI tract, [13,14] it is useful as an adjunct to CKs. |
Special AT-rich sequence binding protein2 (SATB2) | The addition of SATB2 to standard panels showed no significant improvement in sensitivity or specificity in the diagnosis of CRC. [18] As SATB2 expression was positive in 95% of metastatic CRC and 0% of ovarian carcinoma cases, it could be useful as a marker to exclude ovarian carcinomas. [19,20] |
Cadherin 17 (CDH17) | Cadherins are cell–cell adhesion molecules that play important roles in maintaining tissue structure under normal conditions. [21] CDH17 is reportedly expressed in 96%–100% of primary and 100% of metastatic CRC. [25-27] |
Telomerase | Telomerase is a ribonucleoprotein that maintains telomeres by adding TTAGGG repeats onto them. [29] Cancer cells bypass DNA damage-induced inhibitory signaling pathways by upregulating telomerase. Using TBT, telomerase showed 95% sensitivity and 95% specificity in CRC. [32] |
GPA33 (A33) | A33 is expressed in the stomach, small intestine, colon, and rectal epithelial cells. It is expressed in more than 95% of human CRC. [35] Also, an immunohistological study comparing A33 and CDX2 revealed that A33 showed similar sensitivity as but a higher specificity than CDX2 as an immunomarker of CRC. [36] |
Blood biomarker | |
Circulating cell-free DNA (cfDNA) | The cfDNA is released as much larger fragments in tumor cells than in normal cells. [41] Quantitative analysis of circulating cfDNAs by measuring the ratio of longer and shorter DNA fragments, in other words, measuring cfDNA integrity number during the diagnosis of CRC, showed sensitivity of 73%–90% and specificity of 97%–85%. [42,43] |
MicroRNA (miRNA) | The miRNAs are 18–25 bp-long small noncoding RNAs that regulate gene expression by binding to mRNA. [47] Compared to mRNA, miRNAs show higher stability in the blood. Different combinations of miRNA showed high sensitivity and specificity for detecting CRC. [52,53] |
Long noncoding RNA (lncRNA) | HIF1A-AS1 showed high diagnostic ability of CRC with an AUC of 0.960. CRC patients with high HIF1A-AS1 expressions were associated with shorter 5-year survival rate than those with low HIF1A-AS1 expression. [56] |
CRNDE-h showed better diagnostic value compared to CEA. When combined with CEA, he diagnostic value improved. [57] | |
Other markers such as NEAT1, ZFAS1, and GAS5 showed promising results for potential use as a diagnostic or prognostic marker. | |
Insulin-like growth factor binding protein 2(IGFBP-2) | An elevated serum IGFBP-2 level is associated with malignancies of the colon, ovary, and prostate as well as other advanced solid tumors. [62-65] Although the sensitivity and specificity of IGFBP-2 alone is unsatisfactory for early CRC and colon polyp detection, the combination of IGFBP-2 and CEA could increase its sensitivity. [61,66] |
Stool biomarker | |
Guaiac fecal occult blood test (gFOBT) | Use of the gFOBT as a CRC screening test reduced mortality by 11%–33% over 20 years of follow-up. [67-69] However, it cannot distinguish upper GI bleeding from lower GI bleeding or human heme from non-human heme. [70] |
Fecal immunochemical test (FIT) | The FIT detects human globin using a human hemoglobin–specific immunoassay. [72] It has higher sensitivity and specificity than gFOBT for detecting CRC and advanced adenomas. [73] |
Stool DNA (sDNA) | The Cologuard test (multi-target stood DNA test for CRC) showed higher sensitivity than gFOBT and FIT but also a higher false positive rate. [86,87] |
Stool miRNA | miR-92a, miR-21, miR144, miR-106a, miR17-92 cluster, miR135 were up-regulated in CRC, while miR-143 and miR-145 were down-regulated in CRC. [92-94] However, none of the miRNAs showed adequate predictive value for use as a standalone CRC diagnostic test. |
Biomarker | Explanation |
---|---|
Tissue biomarker | |
BRAF | Comprises the mitogen-activated protein kinase pathway, which is associated with cell differentiation, migration, angiogenesis, and proliferation. [95] BRAF mutation is associated with poorer PFS and OS. [99,100] The analysis of its prognostic role is recommended. [101] |
MSI | MSI-high tumors have better prognosis than MSI-low tumors. [97,98] MSI CRC patients showed longer OS and DFS than MSS CRC patients. [110] |
CIMP | The prognostic role of CIMP is unclear. However, the majority of studies reported that CIMP+/CIMP-high CRC patients showed poorer prognosis than CIMP–/CIMP-high CRC patients. [116] |
APC | APC is associated with FAP and most cases of sporadic CRC. [109] APC mutation can cause unregulated transcription of many oncogenes. [117] Patients with APC mutation and high miR-21 reportedly had shorter OS. [118] |
p53 | Some studies reported its association with lower DFS, [103] RFS, [121] and OS [122] rates, but others reported no evidence of a prognostic role. [106,107] |
SMAD4 | SMAD4 mediates the TGF-β superfamily signaling pathway, which is frequently altered in human cancers. [125] Loss of SMAD4 was associated with poor DFS and OS. [129] |
Blood biomarker | |
CEA | CEA level is reportedly significantly associated with patient outcomes. [134] Preoperative CEA level was significantly associated with prognosis in patients with CRC metastasized to the liver. [135,136] |
NLR | Patients with elevated NLR were significantly associated with shorter OS and shorter PFS after treatment. [142] CRC patients with a pretreatment NLR < 5 were more likely to have 5-year OS and DFS. [143] Also, elevated pretreatment NLR was significantly related with poor OS and RFS in patients with liver metastasis. [144] |
cfDNA | CRC patients with higher cfDNA concentrations showed a higher risk of recurrence and shorter OS. [44,128] Detectable APC, KRAS, and p53 mutations in the serum were significantly associated with a higher rate of postoperative metastasis/recurrence. [146] |
Biomarker | Explanation |
---|---|
Tissue biomarker | |
KRAS, NRAS | KRAS proto-oncogene encodes a GTPase protein (KRAS) that plays an essential role in many molecular pathways including the EGFR pathway. [149] Only wild-type RAS tumors showed the clinical benefit of anti-EGFR antibody therapy. KRAS mutations can be used as a negative predictive factor of a response to EGFR inhibitors. [150-153] |
BRAF | It has been reported that there is insufficient evidence that BRAF mutation could be used as a predictive marker for the benefit of anti-EGFR antibody therapy. [155] |
PIK3CA | Results are contradictory about whether PIK3CA mutation is associated with poor PFS and OS in KRAS wild-type CRC patients. [159,160] |
Blood biomarker | |
cfDNA | The cfDNA concentration decreased after primary resection, but when the CRC relapsed, cfDNA levels dramatically increased. [45,145] Similar results were found in rectal cancer patients who underwent chemoradiotherapy: The cfDNA concentration decreased in responders but increased in nonresponders. [165] |
CRC, colorectal cancer; TBT, Telomerase Biosensor Technology; mRNA, messenger RNA; HIF1A-AS1, hypoxia-inducible factor 1alpha-antisense RNA 1; AUC, area under the curve; CRNDE-h, colorectal neoplasia differentially expressed-h.
PFS, progression-free survival; OS, overall survival; MSI, microsatellite instability; CRC, colorectal cancer; DFS, disease-free survival; MSS, microsatellite stable; CIMP, cytosine preceding guanine island methylator phenotype; FAP, familial adenomatous polyposis; RFS, relapse-free survival; TGF-β, transforming growth factor-β; NLR, neutrophil-to-lymphocyte ratio.
EGFR, epidermal growth factor receptor; PFS, progression-free survival; OS, overall survival; CRC, colorectal cancer; cfDNA, cell-free DNA.