Genetic Variants and Colorectal Cancer Risk

Colorectal cancer (CRC) arises through a combination of inherited and acquired genetic alterations that disrupt key pathways of DNA repair, cell growth and immune surveillance. Germline variants in high-penetrance genes such as APC, MUTYH and the mismatch repair genes MLH1, MSH2, MSH6 and PMS2 confer elevated lifetime risk, often manifesting as polyposis syndromes or Lynch syndrome. Genome-wide association studies have also identified common single-nucleotide polymorphisms in loci including SMAD7 and TGF-β signalling components, which modulate sporadic CRC susceptibility. Somatic mutations accumulate over time, producing distinctive tumour mutational signatures that reflect defective repair processes, such as base excision repair failure in MUTYH-associated cases. Advances in multigene panel testing and tumour sequencing have broadened the detection of pathogenic variants, uncovering digenic interactions and informing personalised surveillance and treatment strategies. Integrating germline and somatic data enhances risk stratification, guides chemoprevention and underpins global efforts to tailor CRC screening and therapy.

Research from Nature Portfolio

Recent studies have shown that individuals with biallelic MUTYH mutations exhibit a two- to fourfold increase in somatic base substitution rates across multiple normal tissues, reflecting widespread base excision repair deficiency and yielding characteristic C→A mutation signatures. Variation in mutation burden and signature profiles among individuals suggests allele-specific and modifier gene effects, which may explain differences in adenoma onset and cancer progression. Complementing this, tumour sequencing efforts have established a mutational signature classifier that accurately discriminates colorectal cancers caused by biallelic MUTYH variants from non-MUTYH cases with near-perfect sensitivity and specificity. This approach reclassifies variants of uncertain significance and links pathogenic MUTYH status to recurrent somatic hotspots in KRAS and PIK3CA, offering a robust tool for stratified diagnostics in routine tumour profiling.

Genetic Variants and Colorectal Cancer Risk publication trend

The graph below shows the total number of articles in genetic variants and colorectal cancer risk across all publications each year (not limited to Nature Index journals).

Technical terms

Germline variant: A heritable DNA alteration present in all cells, which may increase cancer susceptibility.

Somatic mutation: A DNA change acquired in non-germline cells, contributing to tumour development.

Biallelic: Pertaining to pathogenic variants in both alleles (copies) of a gene.

Monoallelic: Pertaining to a pathogenic variant in a single allele of a gene.

Base excision repair (BER): A DNA repair pathway that corrects small base lesions, including oxidative damage recognised by MUTYH.

Tumour mutational signature: A characteristic pattern of somatic mutations that reflects specific DNA damage and repair defects.

Multigene panel testing: Simultaneous sequencing of multiple cancer susceptibility genes to identify pathogenic variants.

Variant of uncertain significance: A genetic change whose impact on disease risk remains ambiguous pending further evidence.

References

1. Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors. JCO Precision Oncology (2024).
2. Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells. Nature Communications (2022).
3. Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures. Nature Communications (2022).
4. Multigene Panel Testing Yields High Rates of Clinically Actionable Variants Among Patients With Colorectal Cancer. JCO Precision Oncology (2022).
5. Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer. Genes Chromosomes and Cancer (2020).