Colon Cancer Screen

The value of next-generation sequencing (NGS) in colon cancer risk management

The implementation of precision oncology in South Africa from 2014 using the OncoDEEP NGS assay, provides a transformative approach for managing metastatic CRC with improved clinical outcomes. Microsatellite instability (MSI) and somatic alteration in the BRAF and RAS oncogenes, particularly KRAS-positive genetic alteration present in approximately 40% of CRC cases, are important genetic biomarkers for genomics targeted therapies. Anti–epidermal growth factor receptor monoclonal antibodies combined with chemotherapy improved survival outcomes for patients with wild-type KRAS CRC tumors. Testing of the MSI pathway encompassing 15-20% of sporadic CRC and the majority of hereditary CRC, is focused on the the identification of patients with MSI-high CRC as immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have demonstrated favourable response rates in patients with MSI-high CRC.

NGS-based precision oncology offers a promising first-line treatment for metastatic CRC (1). Significant disparities in biomarker testing highlighted the need for data-driven development of strategies that promote equity in cancer care to outcomes for underserved populations.  Some of the disparities can be explained by differences in access to care and cancer screening, but genetic and environmental factors relating to risk of CRC involving the biology of cancer progression, are important factors to address toward eliminating the disparities identified. All the biological mechanisms driving early-onset CRC are not known, but it appears to be different from those driving older age-of-onset CRCs. As a subset of CRCs is driven by a deficiency in DNA MMR genes causing genomic instability characterised by microsatellite instability (MSI), frequent changes in repeat sequence length in tumor DNA occurs compared with normal tissue. Tumors that exhibit MSI display increased tumor-infiltrating lymphocytes and a Crohn disease–like inflammatory reaction. Although associated with high-grade tumors with poorly differentiated, mucinous, or signet-ring phenotypes, affected individuals have a slightly better prognosis. MSI tumors are more likely to respond to immune checkpoint therapy, possibly due to the generation of excess neoantigens as a consequence of increased genomic instability. In the general population, MSI occurs in approximately 15% of CRCs, which can be hereditary or sporadic. Patients with Lynch syndrome carry a germline mutation in one of the MMR-related genes, and MSI develops when the remaining normal copy of the gene is mutated in a cancer precursor cell. The sporadic form of MSI is more frequently diagnosed in older women as a result of DNA methylation of the MLH1 promoter. DNA sequencing studies using tumour biopsies have not found significant differences between ethnic groups for known cancer driver genes such as KRAS, BRAF, TP53, PIK3CA, and APC; however, cancer mortality remains a persistent difference (2).

  1. Sabbagh et al. Biomarker testing disparities in metastatic colorectal cancer. JAMA Network Open 2024;7(7):e2419142. doi:10.1001/jamanetworkopen.2024.1914.
  2.  Augustus and Ellis. Colorectal cancer disparity in African Americans: Risk factors and carcinogenic mechanisms. Am J Pathol 2018, 188: 291e303;