Unmasking early colorectal cancer clues - in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps

Sep 21, 2026

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Colorectal cancer (CRC) develops from pre-existing colon polyps, with subtype formation shaped by genetic and epigenetic features. CpG island methylator phenotype (CIMP) occurs in about 15–20% of sporadic CRCs and reflects hypermethylation of promoter regions. This study investigates potential prognostic biomarkers by comparing expression and methylation of candidate genes in serrated sessile adenomas/polyps (SSAP) and CRC, aiming to identify which marker better predicts disease.

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CategoryResearch & Report

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Molecular Biology Reports (2024) 51:764 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1033-024-09683-3 ORIGINAL ARTICLE Unmasking early colorectal cancer clues: in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps Seyedeh Nasim Mirbahari1,2,3 · Nayeralsadat Fatemi3 · Sanaz Savabkar3 · Vahid Chaleshi3 · Neda Zali3 · Mohammad Yaghoob Taleghani3 · Ebrahim Mirzaei4 · Leili Rejali3 · Pardis Ketabi Moghadam5 · Ehsan Nazemalhosseini Mojarad5,6 Received: 16 January 2024 / Accepted: 29 May 2024 / Published online: 14 June 2024 © The Author(s) 2024 Abstract Background and aim Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15–20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease. Method This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs) . Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP. Result This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples. Conclusion This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients. Keywords Colorectal cancer · Sessile serrated adenoma polyp · Weissenberg panel · Hyper methylation 􀀍 1 2 3 Ehsan Nazemalhosseini Mojarad [E.nazemalhosseini@sbmu.ac.ir](E.nazemalhosseini@sbmu.ac.ir) Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4 Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran 5 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P. O. Box: 1985717413, Tehran, Iran 6 Department of Surgery, Leiden University Medical Center, P.O. Box 2333 ZA Leiden, Netherlands Abbreviations CRC CIMP SSAP CIN MSI DNMTs NBI PcG APC BRCA1 CDH1 CDKN2AMLH1 PTEN TP53 VHL GEO GEPIA BP MF KEGG DAVID CC CACNA1G IGF2 SOCS1 Colorectal cancer CpG island methylator phenotype Serrated sessile adenomas/polyps characteristics are chromosom

FAQs

What was the study’s main goal regarding early CRC?

To identify prognostic genes by comparing gene expression and methylation status in serrated sessile adenomas/polyps (SSAP) and colorectal cancer, and to determine which marker better predicts disease.

How were candidate genes selected for further investigation?

Two gene expression datasets were analyzed using R and the Limma package to identify differentially expressed genes, then Venn diagram analysis refined the selection to four genes from the Weissenberg panel.

What did the in silico and in vitro analyses show about the four key genes?

The study found four highly downregulated genes (CACNA1G, IGF2, MLH1, SOCS1). In vitro analysis showed they are hypermethylated in both SSAP and CRC samples, while their expression decreased only in CRC samples.

How might methylation and expression data improve prognosis?

The conclusion suggests that decreases in gene expression may help determine whether a polyp becomes cancerous, and combining methylation status with gene expression status in prognostic tests may yield better patient outcomes.

Sep 21, 2026

Uploaded by Violet