Genetic variant linked to liver injury after chemotherapy in colorectal cancer patients

A new international study led by Mayo Clinic researchers has identified a genetic factor that may explain why some patients with colorectal cancer that has spread to the liver experience more severe liver damage after chemotherapy.

For patients with colorectal liver metastases, surgery offers the best chance of long-term survival. To improve outcomes, many patients receive chemotherapy before surgery. While this approach can shrink tumors to make them more operable, one potential side effect is injury to the liver. Until now, it hasn't been clear why certain patients' livers are more prone to chemotherapy-associated liver injury.

"This is the first study to clearly show that a genetic predisposition plays a significant role in how the liver tolerates chemotherapy," says Patrick Starlinger, M.D., Ph.D., a Mayo Clinic Comprehensive Cancer Center hepatobiliary and pancreas surgeon and senior author of the study published in The Lancet eBioMedicine.

In this study, the researchers reviewed 551 patients who had chemotherapy followed by surgery to remove the tumor. They looked at liver health tests to see how chemotherapy affected liver function and genetic markers that are already linked to liver disease in other settings. 

They found that a specific gene variant in the PNPLA3 gene, which is known to affect fat metabolism in the liver, was strongly linked to liver injury after chemotherapy. Patients with two copies of this variant were especially vulnerable, and all of them developed signs of significant liver injury after chemotherapy.

Genetic differences help explain global variation

According to Dr. Starlinger, the PNPLA3 variant is common worldwide, but its prevalence differs by population. For example, in Japan, the mutation is present in more than 41% of the population. It's found in more than 71% among people of Peruvian descent, but fewer than 10% of people in some European populations have it.

Because the genetic variation is more common in certain groups, such as people of Asian or Latin American descent, this may help explain why previous studies in different countries have reported conflicting results about the benefits of giving chemotherapy before and/or after surgery when treating colorectal liver metastases.

Personalizing care to maximize benefit, minimize risk

The findings suggest that a blood test to check for the PNPLA3 variant, along with monitoring liver health, could help doctors identify patients at higher risk for liver damage from chemotherapy.

These findings offer us insight into how we can adjust treatment strategies to best manage the care for patients diagnosed with colorectal liver metastases, while potentially avoiding a negative side effect of chemotherapy. Chemotherapy may still be an appropriate treatment option, and with this information, we can personalize treatment for each patient - for example, tailoring chemotherapy or allowing more time for the liver to recover before surgery."

Patrick Starlinger, M.D., Ph.D., senior author of the study