image: Graphical overview of the study design and colorectal cancer risk stratification using blood-detected mosaic chromosomal alterations (mCAs). The schematic summarizes mCA detection and genomic features, factors associated with mCA carriage, and the integration of mCAs with germline polygenic risk and lifestyle factors for colorectal cancer risk assessment.
Credit: ©Science Bulletin
Colorectal cancer is one of the most common cancers worldwide and a leading cause of cancer-related mortality. More precise risk stratification could support more targeted screening and prevention by identifying individuals at higher risk. Polygenic risk scores are increasingly being explored for this purpose, but they primarily capture inherited genetic susceptibility. Lifestyle factors such as smoking and drinking also contribute to colorectal cancer risk, but self-reported exposures may be affected by measurement error and recall bias and may not fully reflect cumulative exposure over time. Mosaic chromosomal alterations (mCAs) are large-scale somatic chromosomal changes that arise after conception and can be detected in blood-derived DNA. They include chromosomal gains, losses, and copy-neutral loss of heterozygosity (CN-LOH). Because mCAs accumulate with advancing age and may be influenced by lifestyle and environmental exposures, they may capture aspects of biological risk that are not reflected by inherited genetic variation alone. However, their associations with colorectal cancer risk and their value for risk stratification beyond germline genetic susceptibility and lifestyle exposures have remained unclear.
To address this question, researchers from Wuhan University and collaborating hospitals conducted a large multicenter case-control study involving 17,415 Chinese participants, including 7764 colorectal cancer cases and 9651 cancer-free controls. Among the participants, 604 carried autosomal mCAs, representing 3.47% of the study population. Mosaic loss of chromosome X (mLOX) was identified in 433 of 6741 women, while mosaic loss of chromosome Y (mLOY) was identified in 711 of 10,674 men. The overall genomic patterns were broadly similar to those reported in the UK Biobank and BioBank Japan, although some population-specific differences were observed. Increasing age was associated with a higher likelihood of carrying mCAs, while smoking and drinking were also associated with a greater likelihood of mCA carriage.
The researchers then examined the relationship between mCAs and colorectal cancer. Carrying any autosomal mCA was associated with a 22% higher risk of colorectal cancer, while CN-LOH, mLOX, and mLOY were each associated with increased risk. The associations were generally stronger for expanded mCAs, with expanded CN-LOH, expanded mLOX, and expanded mLOY each associated with higher colorectal cancer risk than observed in non-carriers.
The researchers next assessed whether mCAs could further distinguish colorectal cancer risk within strata of inherited genetic susceptibility and lifestyle exposures. Across polygenic risk strata, expanded mCAs further identified subgroups with higher colorectal cancer risk estimates, particularly among participants with high polygenic risk. Similar risk stratification analyses were conducted within smoking and drinking strata. They then combined polygenic risk with smoking and drinking status to define three levels of combined genetic and lifestyle risk. Across these risk groups, expanded mCAs further distinguished colorectal cancer risk, with the highest risk estimates observed among participants in the high combined-risk group who carried expanded events. Specifically, participants in the high combined-risk group who also carried expanded CN-LOH, expanded mLOX, or expanded mLOY had the highest colorectal cancer (CRC) risk estimates compared with those in the low combined genetic and lifestyle risk group without the corresponding mCA event (CN-LOH: OR = 6.53, 95% CI: 2.41–22.80; mLOX: OR = 6.89, 95% CI: 2.52–24.18; mLOY: OR = 3.12, 95% CI: 2.12–4.67).
Overall, these findings suggest that blood-detected mosaic chromosomal alterations (mCAs) may complement inherited genetic susceptibility and lifestyle information in colorectal cancer risk assessment, providing a basis for further investigation of their potential as biomarkers for more individualized risk stratification.