Genomic profiles and their associations with microsatellite instability status, tumor mutational burden, and programmed death ligand 1 expression in Chinese patients with colorectal cancer

Background: Colorectal cancer (CRC) is among the most prevalent malignancies globally, with a rising incidence observed in younger demographics. Despite surgical resection remaining the cornerstone of treatment, metastatic CRC poses significant therapeutic challenges. Immunotherapy, a mode of treatment that leverages the patient's immune system, presents a promising frontier in CRC management, particularly for late-stage cases with limited treatment options. The study was aimed to elucidate the relationships between genetic profiles and predictive biomarkers in CRC patients to inform immunotherapy decisions and improve outcomes.

Methods: We conducted a large-scale study involving 660 patients with CRC, analyzing genetic profiles and predictive biomarkers for immune checkpoint inhibitors (ICIs) using next-generation sequencing (NGS) and immunohistochemistry (IHC). The study focused on assessing the association between gene mutations and markers such as microsatellite instability (MSI) status, tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1) expression.

Results: Analysis revealed a diverse mutational landscape in CRC, with TP53 (73.64%), APC (67.58%), and KRAS (46.82%) being the most frequently mutated genes. We observed significant associations between KRAS mutations and co-occurrences with FBXW7, PIK3CA, and SMAD4 mutations, while KRAS mutations were mutually exclusive with TP53 mutations. KRAS mutations were enriched in the PD-L1 tumor proportion score (TPS) ≥1% population (P=0.03), whereas APC mutations were enriched in the PD-L1 TPS <1% population (P=0.10) as compared to their wild types. Additionally, specific mutations such as KRAS p.A146T, PIK3CA p.H1047R, and BRAF p.V600E were significantly associated with higher TMB and MSI-high status, indicating potential benefits from ICI therapy.

Conclusions: Our findings underscore the importance of genetic profiling in guiding treatment decisions for patients with CRC, particularly in the era of immunotherapy. Understanding the complex interplay between genetic alterations and immune markers is critical for optimizing therapeutic strategies and improving clinical outcomes. Further research is warranted to validate these findings and explore personalized treatment approaches in CRC.