Colorectal cancer (CRC), a type of cancer that affects the large intestine and rectum, is one of the leading causes of cancer-related deaths worldwide.

The mutational landscape of CRC is well characterised, revealing key pathogenic genetic abnormalities that drive carcinogenesis (cancer development) and disease progression.

Moreover, a step-wise colorectal carcinogenesis model has been proposed wherein normal epithelial cells transition to adenoma (non-cancerous tumour) and then to carcinoma (cancerous tumour) as they sequentially acquire genetic mutations.

Mutations in APC, TP53, KRAS, and PIK3CA genes have been frequently reported in CRC patients and have been shown to drive tumour formation.

However, the frequency of these mutations varies with the location of the tumour; APC and TP53 mutations are more frequent in left-sided colon cancer, whereas KRAS mutations are more frequent in right-sided colon cancer.

Additionally, the location of the tumour also influences its morphology, immune cell filtration, prognosis, metastasis, and treatment response, suggesting that mechanisms underlying tumour development are likely site-specific.

Recently, BRAF mutations have been implicated in the development of tumours with a low frequency of APC, TP53, KRAS, and PIK3CA mutations.

These tumours are known to develop via alternate genetic and epigenetic mechanisms, also known as the ‘serrated pathway.

’ An alternate carcinogenesis model based on BRAF mutations, microsatellite instability (MSI), and CpG island methylator phenotype status has been proposed, although the underlying mechanisms remain unknown.

To bridge this gap, a team of researchers led by Dr. Hideyuki Saya, Director of the Oncology Innovation Centre, Fujita Health University, Japan, including Associate Professor Tetsuya Takimoto, Dr. Yuko Chikaishi, and Dr. Hiroshi Matsuoka, analysed CRC tumours with high tumour mutation burden (TMB) to characterise BRAF-associated mutations and decipher their role in the carcinogenesis of tumours lacking major driver oncogenes.

Giving further insight into their work, in a study published in Cancer Science on January 16, 2025, Dr. Saya explains, “We observed that CRCs arising in the right and left colon differ in both their oncogenic mechanisms and biological characteristics. As a result, treatment approaches should also differ. Genome analysis for each cancer type can guide treatment selection and help improve the outcomes of patients with CRC.”

The researchers performed targeted exome sequencing—a gene sequencing technique used to analyse protein-coding regions of the genome using tumour samples obtained from 150 patients with CRC.

They used a proprietary in-house cancer genome analysis system and assessed the type and frequencies of gene mutations based on TMB, MSI, and tumour site.

14 tumours were classified as TMB-high.

Notably, 12 out of 14 tumours were located in the right colon and had a high BRAF mutation frequency and high MSI.

Further, a high TMB was significantly associated with higher age and MSI-high status.

Additionally, mutations in DNA damage response transducers, such as ATM and POLE, and mismatch repair pathway genes MSH2 and MSH6, were frequent and significantly associated with a high TMB.

Mutational signature analysis revealed that these mutations likely precede BRAF mutations associated with the activation of the serrated pathway, suggesting their potential role in early carcinogenesis.

While TMB-high tumours did not harbour APC, TP53, or KRAS mutations, the analysis revealed mutations in genes for pathways related to these key oncogenes, including mutations in receptor tyrosine kinase (RTK)-RAS pathway genes, BRAF, phosphatidylinositol 3-kinase (PI3K) pathway genes, PTEN, and NOTCH pathway genes; these mutations likely contribute to tumour survival and maintenance.

Overall, these findings suggest that TMB-high CRC tumours likely arise from a heterogeneous population of cells that harbours numerous gene mutations distinct from the driver oncogenes.

The researchers thus speculate that these TMB-high tumours rely on alternate gene mutations which may respond well to targeted treatments and immunotherapies.

Sharing his concluding thoughts, Dr. Saya says, “Currently, cancer genome analysis is performed only for a subset of cancer patients. However, in the future, it could well become a standard test for all cancers to better understand their genomic characteristics and devise appropriate treatment strategies.”

Currently, the team is optimising the in-house cancer genome analysis system to integrate it into the diagnosis of CRC and tailor treatments based on genetic mutations.

In the long term, these efforts could pave the way to several advancements in precision oncology.

Source: Fujita Health University