Inherited DNA May Hold the Key to Stopping Cancer Spread

For decades, scientists have focused on understanding how cancer spreads, or metastasizes, which is responsible for the majority of cancer deaths. Historically, most research has zeroed in on the tumor itself—analyzing the mutations within its DNA to identify drivers of metastasis. Despite extensive efforts, no specific tumor mutations have consistently explained why some cancers spread.

New research has taken a fresh approach, investigating whether inherited genetic variations in patients—rather than mutations within tumors—could play a key role in metastasis. A study published in Cell has revealed the first evidence that certain inherited genetic traits can influence the likelihood of breast cancer spreading, introducing a potential new avenue for treatment and prevention.

The research identifies a common variant of the PCSK9 gene, found in the germline DNA of many patients, as a potential driver of metastasis. This variant is particularly widespread among white women, with about 70% carrying it. Data from human studies suggest that patients with this genetic variant are significantly more likely to experience metastasis, with a 22% chance over 15 years, compared to only 2% among patients without it.

Further investigation using mouse models confirmed that the PCSK9 variant promotes cancer spread. Researchers found that the gene variant affects a receptor, LRP1, on cancer cells. This interaction appears to activate processes that encourage metastasis. Interestingly, prior research on melanoma had uncovered a similar connection, where genetic factors influencing metastasis also acted on LRP1, suggesting this receptor plays a recurring role in cancer progression.

What makes these findings particularly exciting is the potential for intervention. A drug already approved to treat high cholesterol—an antibody that blocks PCSK9 activity—could potentially be repurposed to reduce the risk of metastasis in patients with this variant. While clinical trials are needed to confirm its effectiveness in cancer, the safety and tolerability of this drug offer a promising starting point for proactive treatment.

Though these discoveries are groundbreaking, the researchers emphasize that most patients with early-stage breast cancer carrying the PCSK9 variant will not experience metastasis. However, for the subset of patients at higher risk, this research could lead to tailored therapies that target the underlying genetic drivers of metastasis, ultimately saving lives.

This work highlights the importance of looking beyond the tumor itself to better understand cancer’s spread. With funding from the Hess Family Foundation and the National Cancer Institute, the study has opened new doors for exploring how a patient’s inherited DNA shapes their cancer journey.