Abstract
Background:The development of colorectal carcinoma (CRC) involves many genetic and epigenetic alterations and methylation being an important epigenetic event has been described as a diagnostic and prognostic biomarker. Secreted Frizzled- Related Protein 1 (SFRP1) gene regulates diverse physiological processes via the Wnt signaling. Promoter hypermethylation of SFRP1 gene is an epigenetic regulation mechanism that downregulates SFRP1 protein level in the tumor, and happens to be one of the significant events in colorectal carcinogenesis. We studied the clinicopathological relationship of CRC including survival outcomes with SFRP1 gene promoter methylation.Methods:We evaluated promoter methylation status of SFRP1 gene by methylation-specific PCR (MS-PCR) in the tumor tissue in 54 cases of stage II-III CRC patients in north India. The MS-PCR result was further validated by bisulfite sequencing.Results:SFRP1 gene was methylated in 72.2% cases and un-methylated in 27.8%. We found, that SFRP1 gene methylation in tumor was associated with lymph node invasion (p=0.05). The mean overall survival was 22.318 months and 45.173 months respectively for patients with methylated and unmethylated SFRP1 gene (p= 0.010, log rank test), (HR = 17.313, 95% CI: 2.021-148.290 P=0.009).Conclusion:Study indicates that promoter methylation of SFRP1 gene is associated with lymph-node metastasis and poor mean overall survival and it can be a prognostic marker in CRC.
Highlights
Colorectal carcinoma (CRC) is one of the leading causes of mortality worldwide
Study indicates that promoter methylation of Secreted Frizzled- Related Protein 1 (SFRP1) gene is associated with lymph-node metastasis and poor mean overall survival and it can be a prognostic marker in CRC
CpG islands are susceptible for methylation and since most of gene promoter regions are CpG island rich, it implies that promoter regions are most susceptible for hypermethylation and promoter methylation leads transcriptional silencing of the gene (Nandakumar et al, 2011)
Summary
Colorectal carcinoma (CRC) is one of the leading causes of mortality worldwide. It is the third most common cancer in males and second in females globally and recorded as second major cause of cancer-related deaths worldwide (Bray et al, 2018). Β-catenin dependent canonical WNT signaling maintains crypt stem cell compartment in the intestine but overactivation of this pathway by genetic or epigenetic changes has been seen in colorectal carcinoma (Novellasdemunt et al, 2015). This Wnt/βcatenin pathway plays important role in tumorigenesis of several other types of cancers like breast, ovarian, gastrointestinal cancer (Clevers and Hans, 2006; Huang et al, 2006; Zhan et al.,2006). Promoter hypermethylation of SFRP1 gene is an epigenetic regulation mechanism that downregulates SFRP1 protein level in the tumor, and happens to be one of the significant events in colorectal carcinogenesis. Conclusion: Study indicates that promoter methylation of SFRP1 gene is associated with lymph-node metastasis and poor mean overall survival and it can be a prognostic marker in CRC
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