Methylated Septin 9 and Carcinoembryonic Antigen for Serological Diagnosis and Monitoring of Patients with Colorectal Cancer After Surgery

Abstract

With the increasing incidence and mortality of colorectal cancer (CRC), early and accurate diagnosis is of paramount priority to combat this cancer. Epigenetic alterations such as DNA methylation are innovative biomarkers for CRC, due to their stability, frequency, and accessibility in bodily fluids. In this study, blood samples were prospectively collected from patients before and after operation for CRC for determination of methylated septin 9 (mSEPT9) and compared to carcinoembryonic antigen (CEA). The sensitivity of using mSEPT9 methylation status for diagnosing CRC was significantly higher than using elevated CEA levels (73.2% vs 48.2%; p value < 0.001). The sensitivities of both tests increased with higher tumor staging (P = 0.004 and 0.04 respectively). Combined mSEPT9 and CEA had higher accuracy than single CEA or mSEPT9 (P = 0.009 and 0.532 separately). An increase in the methylation level of mSEPT9 detected in the post-operative samples was associated with a higher mortality rate (15.2% vs 1.8%; P = 0.024) and the presence of metastasis (27.3% vs 7.0%; P = 0.013). mSEPT9 was more sensitive than CEA for diagnosing CRC, and combined mSEPT9 and CEA was more accurate. After curative resection, detection of increased mSEPT9 methylation level may indicate adverse outcomes.

Current Update of Laboratory Molecular Diagnostics Advancement in Management of Colorectal Cancer (CRC)

“…The role of mSEPT9 in the screening of CRC is well established, but its prognostic role remains unclear. A recent study by Ma and co-workers linked higher levels of mSEPT9 in post-surgery CRC patients to higher cancer recurrence [43]. If validated by future studies, the same FDA-approved kit can be conveniently used in both screening and prognostic tests without extensive optimizations.…”

“…Significant correlations with known CRC biomarkers such as MSI-H, KRAS, and BRAF mutations were also reported [100]. A simplified summary of the biomarkers reviewed in Sections 2.1-2.4 is presented in Figure 2 [18,19,43 Recently, the possibility for the consensus molecular subtypes (CMS) of CRC to be used as biomarkers was explored. The subtypes are grouped into four based on the tumor gene expression pattern and are described as: (1) CMS1-strong immune activation, hypermutated, and MSI-H; (2) CMS2-epithelial and canonical with marked WNT and MYC signaling; (3) CMS3-epithelial with evident metabolic dysregulation; and (4) CMS4-mesenchymal with stromal invasion, angiogenesis and prominent transforming growth factor-β activation [98,99].…”

“…Significant correlations with known CRC biomarkers such as MSI-H, KRAS, and BRAF mutations were also reported [100]. A simplified summary of the biomarkers reviewed in Section 2.1 to 2.4 is presented in Figure 2 [18,19,43,54,56,57,70,74,78,79,88,[91][92][93][94]96,97,[100][101][102][103][104][105].…”

Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

“…The epigenetic landscape of sarcoma tumours has been explored in several studies [ 27 , 28 , 29 , 30 ], and, although a consensus on epigenetic targets, therapies, and biomarkers in sarcoma is yet to emerge, recent perspectives on this area of research have attempted to refine the progress made so far [ 31 , 32 , 33 ]. In the context of liquid biopsy, several methylation sites have been described as predictive of prognosis for colorectal cancer [ 34 ], breast cancer [ 35 ], and liver cancer [ 36 ]. The methylation status of cfDNA can also be predictive for multiple common cancers, allowing population-wide screening of asymptomatic people at risk [ 37 , 38 ].…”

Plasma Lysyl-tRNA Synthetase 1 (KARS1) as a Novel Diagnostic and Monitoring Biomarker for Colorectal Cancer

“…Although the panel biomarkers showed high sensitivity and specificity for diagnosis, due to non-association with clinicopathologic features, specific single biomarkers are needed for improved panel analysis [15]. For example, currently, methylated septin 9 (SEPT9), a Food and Drug Administration (FDA)-approved biomarker [16][17][18], is not only used as single biomarker, but also as panel analysis for higher specific and sensitive diagnosis.…”