Genetic Factors Influencing Liver Damage from Chemotherapy in Colorectal Cancer Patients

A comprehensive international study led by researchers from Mayo Clinic has identified a genetic component that may explain why some patients with colorectal cancer that has metastasized to the liver experience more severe liver damage following chemotherapy. For patients with colorectal liver metastases, surgical removal offers the best chance for long-term survival, often preceded by chemotherapy to shrink tumors and improve surgical outcomes. However, chemotherapy can cause liver injury, and until now, the reasons behind individual differences in liver damage were unclear.

The study, published in eBioMedicine, highlights that genetic predisposition plays a significant role in how the liver responds to chemotherapy. Researchers examined 551 patients undergoing chemotherapy followed by surgery and analyzed liver function tests alongside genetic markers known to be associated with liver disease. The key discovery was a specific variant in the PNPLA3 gene, which affects fat metabolism in the liver. Patients carrying two copies of this risk variant were particularly susceptible, with all such individuals showing notable signs of liver injury after treatment.

Interestingly, the PNPLA3 mutation is prevalent worldwide, but its occurrence varies by population—more than 41% of Japanese, over 71% of Peruvian, and fewer than 10% of some European populations carry the variant. This variation may explain discrepancies in previous studies regarding the benefits and risks of chemotherapy in different ethnic groups.

The findings suggest that screening for the PNPLA3 variant through blood tests, along with monitoring liver health during treatment, could help identify patients at higher risk for chemotherapy-induced liver damage. Personalizing treatment strategies—including adjusting chemotherapy regimens or allowing more recovery time for the liver—may optimize patient outcomes and reduce side effects.

Overall, this research underscores the importance of considering genetic factors to tailor cancer treatment approaches, ultimately aiming to maximize benefits while minimizing harm for patients with colorectal liver metastases. For more detailed information, the study can be accessed through its DOI: 10.1016/j.ebiom.2025.105928.