# Genetic and Epigenetic Mechanisms in Serrated Adenocarcinomas and Classical Colorectal Carcinomas: An In Silico Study

## TL;DR

This study compares genetic and epigenetic differences between serrated and classical colorectal cancers using in silico analysis to identify potential therapeutic targets.

## Contribution

The study identifies novel hub genes and pathways specific to serrated adenocarcinomas, offering new insights into their molecular mechanisms.

## Key findings

- Serrated adenocarcinomas differ significantly in genomic alterations, mRNA expression, and DNA methylation compared to classical CRCs.
- Key hub genes like PSMC1, SNW1, and H3C2 are linked to chromatin regulation and MAPK signaling in SACs.
- Pathways related to cell structure, protein kinase activity, and immunological mechanisms are enriched in SACs.

## Abstract

Serrated adenocarcinoma (SAC) represents a molecularly heterogeneous subtype of colorectal carcinoma (CRC) linked to the serrated pathway. It is aimed to clarify the molecular mechanisms underlying SAC development. Digital slides from The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma Firehose Legacy dataset (632 cases) were reviewed, and cases were classified as SAC, partial-SAC, or classical CRC. Genomic alterations, mRNA expression, and DNA hypermethylation were compared using cBioPortal. Enrichment analyses were performed via WebGestalt, and protein–protein interaction (PPI) networks with hub genes were identified using STRING and Cytoscape. Statistical significance was defined as p < 0.05 and q < 0.05. The results revealed that the groups showed significant differences in the expression of 327 genomic alterations, 20 mRNAs, and 21 methylated genes (p < 0.0001, q < 0.0001). Hub genes were PSMC1, FLT3LG, SNW1, H3C2, H1-2, H2BC14, H1-5, RPS16, SUPT5H, and MYOD1. The pathways associated with differently expressed genes were the following: cell structure and morphology (phagocytic vesicle, microvillus, endocytosis, and immobile cilium), protein kinase activity (particularly MAPK), and immunological mechanisms. The hub genes act as molecular bridges connecting the observed genomic and epigenetic variations, particularly driving chromatin-related regulation and MAPK signaling pathways. In particular, PSMC1, SNW1, H3C2, H1-2, and H2BC14 genes offer promising molecular targets for future therapeutic approaches in SACs.