Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 2 This study will analyze the latest achievements in the research of the genetic mechanism of colorectal cancer, covering high-penetrant single-gene mutations, medium-risk variations, and the increasing evidence of multi-gene risks. By integrating the achievements of multi-gene testing, GWAS, transcriptome association studies and multi-omics analysis, this review will elaborate on the development trend of genetic susceptibility research for colorectal cancer, as well as its impact on risk prediction, clinical treatment and subsequent research directions. 2 Single-gene Susceptibility 2.1 High penetrance syndrom High penetrance single-gene syndrome is the main cause of the risk of hereditary colorectal cancer (CRC). Familial adenomatous polyposis (FAP) is mostly caused by pathogenic variations in the APCgene, which can lead to the growth of hundreds to thousands of colorectal adenomas in people. If left untreated, Colorectal cancer is almost certain to occur (Yurgelun et al., 2017). Lynch syndrome is the most common hereditary CRC syndrome, caused by germline mutations in mismatch repair (MMR) genes such as MLH1, MSH2, MSH6 and PMS2, which can make microsatellites unstable. Significantly increase the risk of colorectal cancer and other cancers (Yurgelun et al., 2017; Hassanin et al., 2022). Other high-penetrance genes related to colorectal cancer include MUTYH (biallelic mutation), BRCA1/2, PALB2, CDKN2A and TP53. However, the cases of disease caused by these genes are relatively rare (Yurgelun et al., 2017; Mason, 2024). After identifying these key genes, the risk of CRC can be divided into two categories: high penetrance and medium penetrance. People with high penetrance mutations have a significantly increased risk of developing CRC throughout their lives. For instance, compared with ordinary people, patients with Lynch syndrome or FAP have a much higher risk of illness, and the cases caused by these syndromes account for a large proportion among patients with early-onset CRC (Yurgelun et al., 2017; Hassanin et al., 2022). 2.2 Clinical characteristics, genetic patterns and evidence from family studies Monogenic CRC syndrome has very obvious clinical symptoms and genetic patterns. The characteristic of FAP is that many people develop a large number of colorectal polyps at an early age during adolescence, and the inheritance pattern is autosomal dominant inheritance. Lynch syndrome is also an autosomal dominant inheritance. It not only makes people prone to early onset of CRC, but also increases the risk of extrabecular cancers such as endometrial cancer. A large number of family studies have shown that a considerable proportion of CRC cases, especially early-onset CRC, are caused by these high-penetrance mutations (Yurgelun et al., 2017; Hassanin et al., 2022). Large-scale clinical studies have found that among unscreened colorectal cancer patients, approximately 10% carry pathogenic germline mutations of cancer susceptibility genes. Among them, patients with Lynch syndrome account for about 3%, and those caused by other high penetrance genes account for about 2% (Yurgelun et al., 2017). It is notable that many people carrying these mutations have no obvious family medical history and no other symptoms that can indicate hereditary cancer. This reflects the importance of genetic testing beyond routine clinical judgment. 2.3 The Importance of molecular diagnostic strategies and early intervention For the susceptibility to single-gene colorectal cancer, molecular diagnostic methods include detecting germline mutations of known high penetrability genes, and identifying Lynch syndrome patients by detecting microsatellite instability (MSI) and MMR defects in tumors (Yurgelun et al., 2017). Nowadays, multi-gene testing is becoming increasingly common, capable of simultaneously detecting multiple susceptibility genes and better identifying high and medium penetrance mutations (Yurgelun et al., 2017). Early detection of monogenic CRC syndrome is crucial for effective treatment. Regular monitoring methods such as colonoscopy and preventive surgery can significantly reduce the probability and mortality rate of CRC in high-risk populations (Hassanin et al., 2022). Incorporating genetic testing into daily clinical diagnosis and treatment, especially for patients with early-onset CRC and those with a family history of the disease, is of great significance for formulating personalized prevention and treatment plans (Yurgelun et al., 2017; Hassanin et al., 2022).
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