Mutational Landscape of Colorectal Cancer

Avishek Roy

Scientific Liaison Manager
4baseCare

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second major cause of cancer-related mortality. In 2018, there were 1.8 million new CRC cases and 881,000 deaths from the disease, accounting for 6.1 percent of new cases and 9.2 percent of deaths, respectively. In 2035, an increase in the incidence trend of 2.5 million cases is expected.

In cases of early diagnosis, surgery alone or in combination with chemotherapy and radiotherapy remains the primary therapeutic option, however, surgery is no longer effective in cases of advanced stages, which account for 25% of CRC cases. Unfortunately, the quick evolution of drug resistance and the likelihood of cancer recurrence might compromise the efficacy of cytotoxic therapy. As a result, alternative therapy approaches for CRC, particularly for metastatic CRC (mCRC), are desperately needed in order to improve overall survival and minimize the severity. The USFDA approved cetuximab as the first targeted drug for CRC in 2004, followed by bevacizumab in the same year. Anti-VEGF antibodies, such as bevacizumab, aflibercept, and ramucirumab; anti-EGFR antibodies, such as cetuximab and panitumumab; and multi-kinase inhibitors, such as regorafenib, are the three types of targeted medicines currently used to treat CRC.

Colorectal cancer mostly arises from the progressive accumulation of somatic mutations within cells. In individuals with CRC, somatic mutations are becoming more useful biomarkers for treatment choices and outcomes. The changed DNA caused by somatic mutations might be a physiologic driver of CRC. The position of somatic mutations, such as within particular APC and TP53 (classical CRC somatic mutations genes), might alter biological processes involved in tumor growth and progression, eventually influencing CRC prognosis.

Comprehensive genomic sequencing (CGS) has the potential to revolutionize the way cancer patients are treated throughout the world.  Projects like The Cancer Genome Atlas (TCGA) and others have examined genetic alterations in various cancer types, including CRC, using next-generation sequencing (NGS) technologies. The ultimate objective of cancer genome profiling is to enable precision oncology medicine, or therapeutic personalization based on the specific genetic alterations of each patient’s tumor. For instance, the value of genomic evaluation of RAS and RAF for advanced CRC patients has been widely accepted since it was reported that tumors with RAS or RAF mutations are resistant to anti-EGFR therapy. Previously, mutations in these genes were only detected in “hotspots” (e.g., KRAS codon 12, 13, or BRAF V600E), but whole exome sequencing (WES) has demonstrated that mutations outside of hotspots can also alter therapy responses.

Next-generation sequencing has identified a diversity of driver mutations in genes and altered signaling pathways in CRC. Liang et al. (2019) looked for somatic single nucleotide (SNV) and copy number variations (CNVs), indels, substantially mutated genes (SMGs), and commonly changed pathways in 17 tumor/normal tissue pairings in order to find new aberrations in CRC carcinogenesis. In 17 tumors studied, a total of 1,637 somatic SNVs were discovered. A considerable number of somatic mutations in CRC have been found due to improvements in whole exome sequencing and whole genome sequencing, including TP53, APC, TTN, KRAS, PIK3CA, SMAD4, FBXW7, and RNF43, which drive the evolution of a malignant CRC.

KRAS mutations were found in 51.9 % of CRC patients’ specimens (N = 13,336) in a recent study. These findings demonstrated that colorectal cancers with KRAS mutations were less likely to be mismatch repair deficient (dMMR). Resistance to targeted therapy with epidermal growth factor receptor (EGFR) monoclonal antibodies was found to be associated with several genetic changes, including KRAS, NRAS, and BRAF mutations, giving a molecular basis for selecting therapeutic drugs in the treatment of metastatic CRC. Similar to the effects of KRAS mutation, patients with BRAF-mutated mCRC do not respond to anti-EGFR monotherapy (panitumumab or cetuximab). Other genetic variants in the EGFR signaling pathways affecting the HER2 and FGFR1 genes were discovered in subsequent research. Changes in the p53, WNT–β-catenin, TGF–, EGFR, and downstream MAPK/ERK and PI3K/Akt signaling pathways were found to be linked to CRC carcinogenesis, according to genomic research.

There are putative driver mutations in 29 genes linked to mismatch repair (MMR) and pathways. CRC formation has been linked to DNA damage response and repair (DRR) disorders (DNA mismatch repair and homologous recombination), chromosomal instability (CIN), and the CpG island methylation phenotype (CIMP). Microsatellite instability is usually caused by mutations in DNA mismatch repair genes (MLH1, MLH3, MSH2, MSH3, MSH6, and PMS2) or hypermethylation of MLH1 (MSI). Microsatellite instability (MSI) CRC was linked to genetic abnormalities in homologous recombination (HR) mechanisms. Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). In certain patients with CRC, genetic or epigenetic modifications of the DNA mismatch repair genes may have prognostic significance. Despite the fact that testing for MMR status in CRC patients is indicated as a workup test to assess the possibility of Lynch syndrome, current research has shown that MSI is a predictive biomarker for immunotherapy.