Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine

Abstract

This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors.No conflicts of interest were declared. mutations in known high-and moderate-penetrance genes [2][3][4] (one in five of those diagnosed at age less than 50) [5][6][7]. For individuals with certain hereditary cancer syndromes, lifetime risks for CRC may approach IO has become a reality in the treatment of patients with hypermutant cancers in general and also in CRC displaying MSI. The activation of the immune system developed in this type of tumors was noted several decades ago by pathologists who observed extensive Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.

Tumour regression after radiotherapy for rectal cancer – Results from the randomised Stockholm III trial

“…However, for individual patients with inherited tumour syndromes, there is a substantial risk of developing CRC with a life time probability of 50-100%, depending on type of syndrome. 24 The hereditary CRC syndromes are divided into polyposis or nonpolyposis syndromes based on the number and histology of polyps in the bowel. Familial adenomatous polyposis (FAP) is recognized by a large amount of polyps throughout the colon, with a high risk of CRC.…”

<p>Matrix Stiffness and Colorectal Cancer</p>

“…Mutations in genes initiate the process of colon cancer, and previous studies have focused on the biochemical aspects of colon cancer cells. 7,8 The role of biomechanics in tumorigenesis has been underestimated. With the development of methodology in colon cancer research, people gradually realized the indispensable role of mechanical factors in the progression of colorectal cancer.…”

Promising Colorectal Cancer Biomarkers for Precision Prevention and Therapy

“…Hereditary CRC syndromes are rare diseases usually caused by germline mutations in oncogenes or in tumor suppressor genes that are crucial in such processes and events, namely colorectal mucosa turnover, cell division, cell cycle, and programmed cell death. The incidence of hereditary CRC syndromes now account for about 10% of all CRCs [52]. Notably, the prevalence of germline mutations is highest (about 16-33%) in CRC patients diagnosed before the age of 50 [53][54][55].…”