Inherited genetics may drive cancer’s spread

US researchers say they have shown for the first time that our genes can promote metastasis, the process by which cancers spread to different parts of the body.

Writing in the journal Nature Medicine, they report that differences in a single gene, carried within a person’s genome from birth, can alter the progression of melanoma, a type of skin cancer, and suggest that these variations may have the same effect on other cancers.

As such, the discovery may transform how scientists think about cancer metastasis, which leads to the majority of cancer deaths, says Sohail Tavazoie, who led the Rockefeller University team.

Metastasis occurs when cancer cells escape the original tissue to establish new tumours elsewhere. Tavazoie says scientists have long suspected – but not been able to show – that these cells, which first emerge due to mutations inside normal cells, gain their travelling ability following further mutations.

His lab previously identified a gene called ApoE, which is present in the DNA of all of the body’s cells before any cancer arises, that can impact the spread of melanoma. There are three different versions of ApoE, in fact, and colleague Benjamin Ostendorf wondered whether this could explain why melanoma progresses differently in different people.

In experiments with mice possessing one of each of the versions of the gene, he and colleagues found tumours in those with ApoE4 grew the smallest and spread the least.

A closer look revealed that ApoE4 is the most effective version of ApoE in terms of enhancing the immune response to tumour cells. Compared to animals with other variants, the mice carrying ApoE4 showed a greater abundance of tumour-fighting T cells recruited into the melanoma tumour, as well as reduced blood vessels.

“We think that a major impact of the variations in ApoE arises from differences in how they modulate the immune system’s attack,” Ostendorf says.

Genetic data from 300+ human melanoma patients supported this. On average, people with ApoE4 survived the longest, and those with ApoE2 the shortest.

This connection suggests that doctors could look at patients’ genetics to assess the risk of their cancer progressing, the researchers say, and even to determine the course of treatment. Those with ApoE4 might respond best to immune-boosting therapies, for example.

“We need to find those patients whose genetics put them at risk for poor survival and determine what therapies work best for them,” Tavazoie says.

And the findings may have implications beyond cancer, he says. Other studies have shown that variations in ApoE contribute to Alzheimer’s disease: ApoE4 aggravates the risk of this neurodegenerative disorder, in contrast to its suppression of cancer progression.