Genomic Alterations in Colorectal Cancer Pathogenesis

Colorectal cancer (CRC) arises through the stepwise accumulation of genetic and epigenetic changes that disrupt key signalling pathways governing cell proliferation, differentiation and apoptosis. Early events often include loss of tumour suppressor genes such as APC, leading to deregulation of Wnt signalling and initiation of adenoma formation. Subsequent activation of oncogenes in the RAS/RAF/mitogen-activated protein kinase (MAPK) axis, most notably KRAS and BRAF mutations, drives adenoma progression and confers resistance to certain therapeutics. Parallel alterations in the phosphoinositide-3-kinase (PI3K)/AKT pathway, primarily through PIK3CA mutations, further enhance proliferative and survival signals. In a subset of CRCs, mismatch-repair deficiency underlies microsatellite instability (MSI), a hypermutation phenotype associated with distinct clinicopathological features and sensitivity to immune checkpoint inhibition. Conversely, chromosomal instability (CIN) contributes to aneuploidy and broad copy number alterations, encompassing amplifications of oncogenes (for example, MYC, EGFR) and deletions of tumour suppressors (for example, TP53, SMAD4). Integration of next-generation sequencing, genome-wide copy number analysis and emerging liquid-biopsy approaches has refined the molecular taxonomy of CRC, identifying novel driver events, co-mutation patterns and potential predictive biomarkers for targeted therapies. This genomic landscape underpins global efforts to tailor diagnostic, prognostic and therapeutic strategies, informing risk stratification and precision medicine in CRC care.

Research from Nature Portfolio

Large-scale sequencing efforts in diverse patient cohorts have sharpened our understanding of mutation prevalence and prognostic impact across canonical CRC genes. A comprehensive analysis of KRAS, NRAS, BRAF and PIK3CA hotspots in over 350 tumours revealed that rare RAS mutations beyond KRAS exon 2 occur in nearly a quarter of exon-2 wild-type cases and are significantly associated with higher metastatic risk, underscoring the need for expanded genotyping panels to guide clinical management. In a separate cohort exceeding 1,000 patients, comparative assessment of mutational spectra highlighted geographic differences in mutation frequencies and correlations with tumour differentiation, anatomical location and age at onset. These studies demonstrate that refined genomic profiling can stratify patients by risk of recurrence and identify subgroups likely to benefit from specific targeted or adjuvant therapies.

Genomic Alterations in Colorectal Cancer Pathogenesis publication trend

The graph below shows the total number of articles in genomic alterations in colorectal cancer pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Microsatellite instability (MSI): A hypermutation phenotype arising from impaired mismatch repair, resulting in accumulation of insertion/deletion errors at short tandem repeat sequences.

Chromosomal instability (CIN): A state of ongoing chromosomal gains and losses leading to aneuploidy and broad alterations in gene copy number.

Copy number aberration (CNA): Genomic segments exhibiting gains (amplification) or losses (deletion) of DNA regions, affecting gene dosage and expression.

RAS/RAF/PI3K pathways: Key signalling cascades regulating cell growth and survival; commonly activated by mutations in KRAS, NRAS, BRAF (MAPK pathway) or PIK3CA (PI3K/AKT pathway).

Next-generation sequencing (NGS): High-throughput DNA sequencing technologies enabling parallel analysis of multiple genes or whole genomes.

Predictive biomarker: A molecular characteristic that forecasts response or resistance to a specific therapy, guiding treatment decisions.

References

1. Mutation status and prognostic values of KRAS, NRAS, BRAF and PIK3CA in 353 Chinese colorectal cancer patients. Scientific Reports (2018).
2. Molecular spectrum of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese colorectal cancer patients: analysis of 1,110 cases. Scientific Reports (2015).
3. Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania. International Journal of Molecular Sciences (2023).
4. The Developing Story of Predictive Biomarkers in Colorectal Cancer. Journal of Personalized Medicine (2019).