Colorectal cancer remains a significant health concern globally. While genetic factors play a crucial role in its development, identifying the exact genes and genetic variations involved continues to be a complex endeavour.
In this article, we look at a recent study published by Law et al., in Nature Genetics has revealed more insights into the molecular profile of colorectal cancer and the genetic factors that could increase colorectal cancer risk (1). Researchers have systematically identified functional variants and effector genes that contribute to the risk of developing colorectal cancer. Thus this research provides further understanding of the genetic profile of colorectal cancer and developing novel therapies.
Contents
Introduction to colorectal cancer
Colorectal cancer is a type of cancer that affects parts of the digestive system —the colon or rectum—and is one of the most common types of cancer worldwide (2). Several risk factors contribute to the development of colorectal cancer, including age (especially over 50), diet high in red and processed meats, obesity, physical inactivity, smoking, and excessive alcohol consumption (3). Genetic factors also play a crucial role and increase the risk of developing cancer. In addition to this, hereditary syndromes such as Lynch syndrome and familial adenomatous polyposis (FAP), caused by genetic changes in genes linked with colorectal cancer significantly increase the likelihood of developing colorectal cancer (3).
Genetics of colorectal cancer
Numerous genes are implicated in the development of colorectal cancer, particularly those associated with hereditary syndromes. Examples of genes include APC (adenomatous polyposis coli), which is often mutated in FAP, leading to numerous polyps which increase the risk of cancer. Other genes such as MLH1, MSH2, MSH6, and PMS2 are crucial in the DNA mismatch repair pathway and are commonly associated with Lynch syndrome, significantly increasing colorectal cancer risk. Additionally, mutations in the KRAS gene can lead to uncontrolled cell division and tumor growth, while alterations in the TP53 gene, which is involved in apoptosis and cell cycle regulation, are also frequently found in colorectal tumors (4).
Treatment approaches for colorectal cancer
Treatment options for colorectal cancer typically involve surgical resection of the tumor, followed by chemotherapy to reduce recurrence risk. Targeted therapies and immunotherapy approved by FDA/EMA are also utilized, especially for tumors with specific genetic mutations or characteristics, providing personalized treatment approaches. Therefore, understanding these genetic factors is essential for effective prevention and clinical management of colorectal cancer (5).
Aim and hypothesis
Previous genome-wide association studies have successfully identified numerous genetic loci—regions in the DNA—associated with colorectal cancer risk (6). However, they did not precisely identify the specific genetic variations that directly cause the disease or the specific target genes that these variants correspond to.
The aim of the study was to identify the specific genetic variations and their corresponding genes that contribute to the development of colorectal cancer. By understanding the genetic mechanisms involved in colorectal cancer, researchers can gain valuable insights into the disease’s development and potentially identify novel therapeutic gene targets.
Methodology and results
The authors employed statistical fine-mapping techniques along with tissue-specific epigenetic annotations and massively parallel reporter assays (MPRA) to narrow down the specific regions within these loci that harbor the causal variants. In total, 170 risk loci were analysed and functional variants linked with colorectal cancer were identified. 40 loci contained individual variants, whereas 98 loci were found to have more than one variant. A multilayered analysis was performed to link those variants to a total of 208 target genes. The genes were then classified into categories according to their biological or cellular function. Cell adhesion, cell cycle, metabolism, gene expression, and cell signalling are only some examples of the categories in which the 208 genes belong.
The authors next sought to identify whether these genes are known to play an important role in colorectal cancer or any other type of cancer. Integrated analysis from available studies in the biomedical literature was performed. Results showed that only some of these genes are known drivers of colorectal cancer, including BCL9L, CDH1, SMAD3, SOX9, TBX3 and TCF7L2. In addition, from the previously identified 208 genes, 142, such as CALML4, CAMK2A, ATXN2, and SLCO2A1, are not known to play a role in colorectal cancer and 47 of these have no established role in any cancer.
The authors also investigated the clinical utility of the identified genes in colorectal cancer therapeutics. Several identified genes already have approved drugs such as crofelemer which targets the ANO1 gene that is overexpressed in colorectal cancer. Additionally, the study highlighted that 44 genes can be promising as potential new drug targets, and 31 genes are likely to be good targets. Based on CRISPR knockout data and patient genomic information, genes such as TBCD, KLF5, SOX9, CCND1, CDH1, MYC, and POU5F1B emerged as strong candidates for therapy in different types of cancer.
Conclusion
Overall, the study represents a significant step forward in our understanding of the genetic basis of colorectal cancer. By identifying causal variants and their target genes, the researchers have opened up new avenues for the development of more effective prevention, diagnosis, and treatment strategies.
References
[1] Law PJ, Studd J, Smith J, Vijayakrishnan J, Harris BT, Mandelia M, Mills C, Dunlop MG, Houlston RS. “Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.” Nat Genet. 2024 Oct;56(10):2104-2111. doi: 10.1038/s41588-024-01900-w. Epub 2024 Sep 16. PMID: 39284974; PMCID: PMC11525171. https://www.nature.com/articles/s41588-024-01900-w.
[2] World Cancer Research Fund International. Worldwide cancer data | World Cancer Research Fund International. WCRF International. World Cancer Research Fund International; 2022. Available from: https://www.wcrf.org/cancer-trends/worldwide-cancer-data/. Accessed 26 November 2024.
[3] American Cancer Society. “Colorectal Cancer Risk Factors.” www.cancer.org. American Cancer Society; 2023. Available from: https://www.cancer.org/cancer/types/colon-rectal-cancer/causes-risks-prevention/risk-factors.html. Accessed 26 November 2024.
[4] National Cancer Institute. “Genetics of Colorectal Cancer.” National Cancer Institute. Cancer.gov; 2019. Available from: https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq. Accessed 26 November 2024.
[5] American Cancer Society. “Colorectal Cancer Treatment | How to Treat Colorectal Cancer.” www.cancer.org. Available from: https://www.cancer.org/cancer/types/colon-rectal-cancer/treating.html. Accessed 26 November 2024.
[6] Fernandez-Rozadilla, C. et al. “Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.” Nat. Genet. 55, 89–99 (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC10094749/.
