Cancer Genetics and Epigenetics 2025, Vol.13 http://medscipublisher.com/index.php/cge © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
Cancer Genetics and Epigenetics 2025, Vol.13 http://medscipublisher.com/index.php/cge © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in cancer genetics, cancer epigenetics, clinical pharmacology, cancer biology at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of Cancer Genetics and Epigenetics Email: edit@cge.medscipublisher.com Website: http://medscipublisher.com/index.php/cge Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Cancer Genetics and Epigenetics (ISSN 2369-2995) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is aimed to publish all works in the areas that with quality and originality, with a scope that spans the areas of cancer genetics and cancer epigenetics. It is archived in LAC (Library and Archives Canada) and deposited in CrossRef. The journal has been indexed by ProQuest as well, expected to be indexed by PubMed and other datebases in near future. All the articles published in Cancer Genetics and Epigenetics are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Cancer Genetics and Epigenetics (online), 2025, Vol. 13, No. 1 ISSN 2369-2995 http://medscipublisher.com/index.php/cge © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Advances in Genetic Susceptibility Studies of Colorectal Cancer: From Single Genes to Polygenic Huixian Li, Jianhui Li Cancer Genetics and Epigenetics, 2025, Vol. 13, No. 1, 1-10 Anti-inflammatory Diets in Pancreatic Cancer Management: Mechanisms and Clinical Evidence JianWang Cancer Genetics and Epigenetics, 2025, Vol. 13, No. 1, 11-20 Emerging Molecular Pathways in Prostate Cancer Development and Their Therapeutic Implications Liting Wang Cancer Genetics and Epigenetics, 2025, Vol. 13, No. 1, 21-31 Study on the Impact of Patient Genotyping on Targeted Therapy for Cervical Cancer Hui Xu Cancer Genetics and Epigenetics, 2025, Vol. 13, No. 1, 32-40 The Role of CRISPR/Cas9 in Targeting HER2-Positive Breast Cancer: Current Research and Future Perspectives Qiyan Lou, Xiaoying Xu Cancer Genetics and Epigenetics, 2025, Vol. 13, No. 1, 41-49
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 1 Review Article Open Access Advances in Genetic Susceptibility Studies of Colorectal Cancer: From Single Genes to Polygenic Huixian Li, Jianhui Li Institute of Life Science, Jiyang College of Zhejiang A&F University, Zhuji, 311800, Zhejiang, China Corresponding author: jianhui.li@jicat.org Cancer Genetics and Epigenetics, 2025, Vol.13, No.1 doi: 10.5376/cge.2025.13.0001 Received: 07 Nov., 2024 Accepted: 18 Dec., 2024 Published: 02 Jan., 2025 Copyright © 2025 Li and Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li H.X., and Li J.H., 2025, Advances in genetic susceptibility studies of colorectal cancer: from single genes to polygenic, Cancer Genetics and Epigenetics, 13(1): 1-10 (doi: 10.5376/cge.2025.13.0001) Abstract This study analyzed the genetic causes of Colorectal cancer (CRC), a disease influenced by multiple factors, in which the role of genetic factors accounted for approximately 35%. The research focuses on the changes in the research direction of this field. In the early stage, it mainly studied single-gene high-penetrance mutations (such as APC and mismatch repair genes), but now it has shifted to studying complex risk situations involving medium-risk variations and a large number of low-penetrance polymorphisms. By studying more than 200 common risk loci identified in genome-wide association studies (GWAS). This study explains how the polygenic Risk Score (PRS) classifies an individual's risk of disease beyond traditional family medical history, also discussed the important role of the research method combining multiple omics such as transcriptomics, epigenomics and microbiomics in deeply understanding the biological pathways of CRC susceptibility and improving the accuracy of risk prediction models. Although there have been many achievements, this study also analyzed the current difficulties encountered in functional verification, applicable population range and clinical application. Finally, this study points out that to achieve breakthroughs in the future, it is necessary to collaborate among different disciplines, increase data on different populations, and integrate artificial intelligence technology. Only in this way can the role of personalized prevention and screening of CRC be fully exerted. Keywords Colorectal cancer (CRC); Genetic susceptibility; Polygenic risk score (PRS); Genome-wide association studies (GWAS); Multi-omics integration 1 Introduction Colorectal cancer (CRC) is a major global health problem and one of the most prevalent types of cancer worldwide, exerting significant pressure on public health efforts, especially in Westernized countries (Lorans et al., 2018). It is estimated that approximately 35% of colorectal cancer cases are related to genetic factors, while high-risk mutations that cause known susceptibility genes such as Lynch syndrome and familial adenomatous polyposis account for 5%~10% of the cases (Pearlman et al., 2017; Lorans et al., 2018). It should be particularly noted that many patients with early-onset colorectal cancer carry pathogenic germline mutations in their bodies. This reflects the key role of genetic factors in the risk of colorectal cancer and also indicates the importance of genetic testing for formulating effective prevention and control strategies (Pearlman et al., 2017; Yurgelun et al., 2017). When the genetic susceptibility of colorectal cancer was initially studied, the main focus was on high penetrance mutations of single genes, such as mismatch repair genes and APCgenes, which were associated with distinctive genetic syndromes (Chubb et al., 2015; Pearlman et al., 2017; Lorans et al., 2018). Later, the emergence of multi-gene detection technology expanded the scope of research and enabled the detection of high and medium penetrance mutations in more genes (Yurgelun et al., 2017; Pearlman et al., 2017; Lorans et al., 2018). Recently, through genome-wide association studies (GWAS) and multi-omics research methods, more than 200 common genetic variations related to the risk of colorectal cancer have been discovered. Many variations are in non-coding regions and jointly constitute the multi-gene risk status of colorectal cancer (Schmit et al., 2018; Guo et al., 2020; Yuan et al., 2021; Chen et al., 2023; Chen et al., 2024). The polygenic risk score, which integrates the effects of multiple common variations, can now identify the population with a significantly increased risk of colorectal cancer (Schmit et al., 2018; Chen et al., 2024).
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).
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 3 3 The Discovery of Low Penetrance Genes and GWAS 3.1 The contribution of genome-wide association studies (GWAS) to the discovery of CRC-related SNPS Genome-wide association studies (GWAS) have greatly changed people's understanding of the genetic mechanism of CRC by identifying many common low-penetrant single nucleotide polymorphisms (SNPS) associated with the risk of colorectal cancer (CRC) (Ma et al., 2013; Huyghe et al., 2018; Schmit et al., 2018). These studies were carried out in a large population and identified more than 100 independent related signals. This indicates that the characteristic of CRC being prone to onset is related to many genes, and also suggests that both common and rare genetic changes can affect the risk of disease (Huyghe et al., 2018; Schmit et al., 2018). The GWAS research method has also identified risk sites that were previously undetectable by the candidate gene research method, providing new insights into the biological processes involved in CRC, such as immune function, DNA repair, and intercellular signal transduction (Ma et al., 2013; Huyghe et al., 2018; Schmit et al., 2018). With the continuous increase of GWAS research data and the improvement of risk prediction models, it also provides a basis for formulating personalized screening programs through multi-gene risk scores (Schmit et al., 2018). 3.2 Common risk loci and their functional annotations There are some common risk sites that are closely related to colorectal cancer. It is particularly worth mentioning that the genetic changes at the position of 8q24.21 (rs6983267) are more common in patients with a family history of CRC, while the locus 8q23.3 (rs16892766) is associated with advanced tumors (Abuli et al., 2010). Other loci such as 16q22.2 (rs9929218) are associated with colorectal adenoma. In large-scale GWAS comprehensive analyses, loci such as 4q22.2, 5p15.33, 6p21.31 and 11q23 were also discovered (Abuli et al., 2010; Schmit et al., 2018). Studies on the functions of these loci have found that many risk-related genetic changes are in regions that do not encode proteins. They usually act like switches, affecting the activities of nearby genes related to cancer occurrence, DNA repair, and immune responses (Huyghe et al., 2018; Law et al., 2024). Recently, through fine localization and epigenetic studies, specific genetic changes have begun to be mapped to the genes they affect, making the molecular reasons for the high incidence of CRC clearer (Law et al., 2024). 3.3 Cumulative Impact of low-risk variations on individual disease susceptibility Although individual genetic changes with low penetrance only slightly increase the risk of colorectal cancer, because they are common in the population, the combined impact is significant (Houlston and Tomlinson, 2001; Ma et al., 2013). The polygenic risk score combines the effects of multiple common genetic changes to identify individuals with a significantly increased risk of CRC-based on genetic characteristics, up to 4.3% of the population has at least twice the possibility of developing CRC as others (Schmit et al., 2018). Genetic factor analysis shows that these low-risk genetic changes can explain a large part of the risk of familial CRC. Recent studies estimate that common genetic types can explain 14.7% of the difference in the risk of disease among family members (Ma et al., 2013; Schmit et al., 2018). With more and more genetic changes being discovered and incorporated into risk assessment models, the ability to predict the possibility of CRC onset has been continuously enhanced, which also makes personalized prevention and screening programs more achievable (Schmit et al., 2018; Huyghe et al., 2018). 4 Polygenic Risk Score (PRS) 4.1 Construction of the PRS weighted model based on multiple SNPS The polygenic risk Score (PRS) is derived by adding together the effects of many single nucleotide polymorphisms (SNPS) related to the risk of colorectal cancer (CRC), and each snp is assigned different weights according to the degree of influence obtained from genome-wide association studies (GWAS) (Thomas et al., 2020; Duenas et al., 2023; Tamlander et al., 2024). There are many methods for constructing PRS. For example, first select a group of verified CRC-related gene loci, and then use machine learning methods to handle the interrelationships between genes. There is also the Bayesian genome-wide risk prediction model (like LDpred), which can consider more than one million gene changes. Make risk estimation more accurate (Thomas et al., 2020; Duenas et al., 2023).
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 4 Which SNPS are selected and how to assign weights to them have a significant impact on the accuracy of PRS. For instance, the PRS calculated based on 140 known CRC-related gene variations has a less favorable predictive effect compared to the genome-wide PRS calculated based on nearly 1.2 million gene variations. This indicates that in order to accurately predict risks, more SNPS need to be taken into account and good modeling methods should also be used (Thomas et al., 2020; Duenas et al., 2023). 4.2 The predictive value and clinical application of PRS in CRC screening PRS has a certain role in predicting the risk of CRC, but it is not particularly strong. According to different models and populations, its prediction accuracy (measured by the area under the curve AUC) is between 0.61 and 0.71 (Thomas et al., 2020; Duenas et al., 2023; Kim and Chatterjee, 2025). People with a high PRS score have a 2 to 3 times higher risk of developing CRC than the general population. Even if no one in the family has had CRC, high-risk groups who need to have examinations earlier or more can still be identified through PRS (Figure 1) (Frampton et al., 2016; Thomas et al., 2020; Tamlander et al., 2024; Kim and Chatterjee, 2025). Figure 1 Description of three approaches to derive polygenic risk scores (PRS) for colorectal cancer (Adopted from Thomas et al., 2020) If PRS is combined with other traditional risk factors or protein test results, the population can be better classified according to the risk level, and it can also help doctors formulate personalized screening plans, such as deciding when to start the examination or how often to perform colonoscopy (Guo et al., 2020; Guo et al., 2022; Tamlander et al., 2024; Kim and Chatterjee, 2025). Formulating personalized screening plans with PRS can reduce unnecessary examinations for low-risk populations and help doctors detect the conditions of high-risk populations earlier (Frampton et al., 2016; Tamlander et al., 2024; Kim and Chatterjee, 2025). 4.3 Current challenges: population heterogeneity, model validation and generalability One major problem encountered in the practical application of PRS is that there are significant genetic differences among different groups of people. The PRS model developed in a certain population often has poor prediction effects when applied to other populations. This requires the development and validation of specialized models for different groups of people (Thomas et al., 2020; Duenas et al., 2023). For instance, a PRS model based on European population data may not be able to accurately predict the disease risk of East Asians or other non-European populations. Therefore, when developing and validating the model, it is essential to use data with a genetic background similar to that of the target population (Duenas et al., 2023; Zhao et al., 2024). In addition, due to differences in research design, selection criteria, and whether non-genetic risk factors were considered, the reliability and applicability of the PRS model have also become issues (Duenas et al., 2023; Jiang et al., 2024). Further research is needed to improve the PRS model, verify its accuracy in different populations, and combine PRS with factors such as clinical conditions and living habits. Only in this way can it play a better role in the actual CRC screening program (Duenas et al., 2023; Tamlander et al., 2024; Jiang et al., 2024; Kim and Chatterjee, 2025).
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 5 5 Comprehensive Omics Approach 5.1 Epigenetic regulation (such as DNA methylation) and gene-gene interactions Epigenetic changes, especially DNA methylation, play a significant role in making people prone to colorectal cancer (CRC). It can affect the activity of genes and promote tumor formation. Analyzing the gene expression data and DNA methylation data together has discovered many genes that may make people prone to CRC. Studies have shown that many gene changes identified through genome-wide association studies (GWAS) affect gene regulation through epigenetic mechanisms (Yuan et al., 2021). For instance, excessive DNA methylation and alterations in gene expression patterns can change the activity patterns of cells, such as enhancing their mobility and invasion capabilities, which is crucial for the development of CRC (Yuan et al., 2021; Yao et al., 2022). The mutual influence among genes makes the genetic situation of CRC more complex. Studies have found that the interaction between genetic changes and epigenetic changes can disrupt key processes of cancer cell growth, such as MAPK and PI3K-Akt signaling, thereby affecting whether a person will develop CRC (Zhang et al., 2023). These findings indicate that to clarify the risk of CRC, both genetic and epigenetic factors need to be considered simultaneously. 5.2 Integrate multi-omics data to enhance the accuracy of risk prediction The integration of data from genomics, transcriptomics, proteomics, metabolomics and microbiomics has greatly promoted the discovery of new CRC biomarkers and made the disease risk prediction model more accurate (Ullah et al., 2022; Bischof et al., 2024). The multi-omics research method can capture the complex interrelationships among different molecular levels, enabling a comprehensive understanding of the diversity of CRC, which cannot be achieved by studying a single type of data alone (Figure 2) (Ullah et al., 2022; Bischof et al., 2024). For instance, by combining the data of the microbiome, metabolome and transcriptome, high-precision models can be created through machine learning for detecting CRC and classifying disease risk levels (Zhang et al., 2022). Figure 2 Graphical representation of different multi-omics-based approaches in discovering novel CRC biomarkers and therapeutic targets (Adopted from Ullah et al., 2022) Comprehensive multi-omics analysis can also help people determine different molecular subtypes (CMS) of CRC, and the key mutations, signal transduction pathways and immune characteristics of each subtype are different (Bischof et al., 2024). Such detailed molecular classification can provide a reference for formulating personalized treatment plans and also make the treatment management of CRC patients more effective (Ullah et al., 2022; Bischof et al., 2024). 5.3 Network biology and pathway analysis of CRC susceptibility Network biology and biopath-based analysis utilize multi-omics data to study the complex molecular interactions that make people prone to CRC. By integrating gene networks and multi-omics data, researchers identified the genes most likely to be associated with CRC risk and clarified the roles of these genes in key biological processes such as cell growth, immune response, and metabolic regulation (Zhang et al., 2023). For instance, through the method of network analysis, it was found that transcription factors such as CEBPB are key factors regulating CRC. By analyzing biological pathways, genetic changes can be linked to actual influences (Zhang et al., 2023).
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 6 Analysis based on biological pathways also found that changes in intestinal microbiota and their metabolites interact with human genes, affecting tumor immunity and therapeutic effects (Zhang et al., 2022). These research results indicate that network and biological pathway analysis have great potential in discovering new therapeutic targets and understanding the causes of CRC from an overall perspective (Zhang et al., 2022; Zhang et al., 2023). 6 Challenges and Future Prospects 6.1 The functional verification is relatively slow; the biological mechanism is still unclear Although genome-wide association studies and multi-gene panel tests can quickly identify genetic changes related to colorectal cancer (CRC), it is relatively slow to figure out exactly what these changes are for. Many genes and locations that have been found to potentially increase the risk of disease, especially those that are less active or not in the coding region, have not yet been clarified exactly how they work. This makes it very difficult to turn these genetic discoveries into an understanding of the causes of diseases or actual treatment methods (Valle, 2014; Yuan et al., 2021). How to determine those genetic changes of unclear significance and exactly what roles they play in the pathogenesis of CRC remains a big problem. It is equally difficult to identify the genes that cause some hereditary CRC syndromes that have not yet been clarified (Valle, 2014; Lorans et al., 2018). The diversity of genes themselves and various risk influencing factors (such as the interactions between genes and between genes and the environment) also make the study of the genetics of CRC more complex. New research tools such as patient tissue models and organoids are expected to help clarify the actual effects brought about by genetic alterations. However, the widespread application of these tools in research and their true effectiveness are still under development (Yuan et al., 2021; Alipourgivi et al., 2023). Continuing to collect a large amount of diverse data and strengthening international cooperation are of great significance for understanding the biological causes of CRC susceptibility (Valle, 2014; Lorans et al., 2018). 6.2 Ethical and practical challenges of personalized screening strategies The development of personalized CRC screening methods based on genetic risk has brought about some important ethical and practical issues. Opinions vary on which genes should be included in the clinical testing portfolio, especially those whose functions have not been fully determined or whose clinical values are unclear. This makes it more troublesome for patients to provide advice and manage risks (Lorans et al., 2018). Furthermore, the discovery of pathogenic gene changes in those who originally did not meet the requirements of traditional testing poses a challenge to the existing guidelines and may lead to too much or too little examination or treatment (Pearlman et al., 2017; Lorans et al., 2018). Practical difficulties also include how to conduct genetic screening fairly among various populations, avoid possible genetic discrimination, and the need for a sufficient number of professional genetic counselors. Conducting large-scale genetic testing requires the coordination of doctors, policymakers and educators to ensure maximum benefits and minimum drawbacks, especially in areas with limited resources (Szuman et al., 2024). Those who make decisions need to give priority to supporting relevant research and infrastructure in order to responsibly apply genetic risk assessment to routine CRC prevention and care (Lorans et al., 2018; Szuman et al., 2024). 6.3 The potential of interdisciplinary collaboration and artificial intelligence-driven research Having experts from different fields work together is increasingly regarded as the key to promoting genetic research on colorectal cancer and applying the findings to clinical practice. To achieve truly effective progress, it requires the joint efforts of geneticists, doctors, bioinformatics experts, social scientists and policymakers to address various issues such as explaining genetic changes, establishing risk models, and caring for patients (Lorans et al., 2018; Szuman et al., 2024). Combining a large amount of data containing multiple information (multi-omics) and building a large biobank will help discover and confirm new susceptibility genes and therapeutic targets (Yuan et al., 2021; Alipourgivi et al., 2023). Artificial intelligence (AI) and machine learning provide powerful tools for analyzing complex genetic and multi-omics data, improving risk prediction models, and identifying new biomarkers for CRC (Yuan et al., 2021).
Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 1-10 http://medscipublisher.com/index.php/cge 7 These technologies can accelerate the speed of clarifying the functions of genetic changes, help develop individualized treatment methods, and ultimately improve the early detection, prevention and treatment strategies of CRC (Yuan et al., 2021; Alipourgivi et al., 2023). 7 Concluding Remarks The research on the genetic risk of colorectal cancer (CRC) is shifting from focusing only on individual gene changes to multi-faceted studies that combine gene, gene activity (transcriptome), and functional data. Recent work has combined genome-wide association studies (GWAS), gene activity association studies (TWAS), and functional experiments to search for new susceptibility genes and understand the biological causes of CRC development. The approach of combining data from different populations and multiple molecular sources is making risk predictions more accurate and laying the foundation for more effective, individualized prevention measures. This multi-faceted research also helps to understand the complexity of CRC, including the different locations of tumor growth and the differences in the ancestral background of the population, which is crucial for improving the targeting of prevention and screening recommendations. As research continues to break through the old framework, this field is moving towards a comprehensive grasp of CRC risks. From identifying significant individual gene variations to developing and using the polygenic Risk Score (PRS), this represents a major change in the research of CRC genes and the way they are treated. Although checking individual genes remains important for identifying patients with genetic syndromes, PRS incorporates the influence of many common minor changes, enabling risk classification for a wider range of people. This change makes risk assessment more detailed and may lead to the formulation of specialized screening and prevention plans based on an individual's overall genetic risk. Adding PRS to the medical treatment model can better predict risks than only looking at family history in the past, and support earlier and more accurate intervention for those at the highest risk. This change also indicates that it is necessary for everyone to collaborate on large-scale research to improve and verify PRS suitable for different populations. In order to truly make good use of genetic information to prevent CRC, high-quality studies involving various ethnic groups must be conducted. Combining and analyzing genetic data from different ancestral backgrounds has made risk prediction better and also indicates that screening programs need to take into account genetic differences among populations. This kind of research conducted among different populations is of great significance for establishing a unified risk assessment model and addressing the health unfairness of CRC outcomes. Continuous collection of large international data and strengthened cooperation will be the key to confirming gene discoveries, improving risk models, and turning the results into effective and fair CRC prevention methods. Acknowledgments We would like to thank Dr. Xuan continuous support throughout the development of this study. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Abulí A., Bessa X., González J.R., Ruíz-Ponte C., Cáceres A., Muñoz J., Gonzalo V., Balaguer F., Fernández-Rozadilla C., González D., De Castro L., Clofent J., Bujanda L., Cubiella J., Reñé J., Morillas J., Lanas Á., Rigau J., García A., Latorre M., Saló J., Bañares F., Argüello L., Pena E., Vilella À., Riestra S., Carreño R., Payá A., Alenda C., Xicola R., Doyle B., Jover R., Llor X., Carracedo Á., Castells A., Castellví-Bel S., and Andreu M., 2010, Susceptibility genetic variants associated with colorectal cancer risk correlate with cancer phenotype, Gastroenterology, 139(3): 788-796. https://doi.org/10.1053/j.gastro.2010.05.072 Alipourgivi F., Motolani A., Qiu A.Y., Qiang W., Yang G., Chen S., and Lu T., 2023, Genetic alterations of NF-κB and its regulators: a rich platform to advance colorectal cancer diagnosis and treatment, International Journal of Molecular Sciences, 25(1): 154. https://doi.org/10.3390/ijms25010154 Bischof J., Woodsmith J., and Church D., 2024, Abstract 409: deciphering chromosomal instability in consensus molecular subtypes (CMS) in CRC: Insights from an integrative multi-omics approach, Cancer Research, 84(6_Supplement): 409-409. https://doi.org/10.1158/1538-7445.am2024-409
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