Study Provides First Evidence That Cancer Metastasis Is Influenced By Inherited Genes

The researchers carried out a series of experiments in melanoma-bearing mice that carried human variants of the APOE gene. The results showed that tumors in animals carrying APOE4 grew more slowly, and spread less than those in APOE2 variant mice.

Animal and human studies by scientists at Rockefeller University have for the first time generated data to suggest that an individual’s pre-existing genetic make-up may impact the likelihood of cancer progressing and metastasizing.

The researchers discovered that melanoma-bearing mice carrying the APOE4 variant of the APOE gene were less likely to develop metastases than animals carrying the APOE2 variant.

APOE4 variant melanoma-bearing mice also survived for longer, and responded better to immune checkpoint therapy than APOE2 mice.

An analysis of data from human cohorts similarly showed that melanoma patients who carried the APOE4 variant had improved survival compared with those carrying APOE2.

The scientists say they suspect that these inherited variations can have the same effect on other types of cancer.

“Patients often ask ‘Why am I so unlucky? Why did my cancer spread?’” noted lead investigator Sohail Tavazoie, MD, Leon Hess professor and senior attending physician.

“As doctors, we never had an answer. This research provides an explanation,” Tavazoie suggests that the discovery may change the way that scientists think about cancer metastasis, and lead to a better understanding of patients’ risks, helping to inform on treatment decisions.

The team reported its findings in Nature Medicine, in a paper titled, “Common germline variants of the human APOE gene modulate melanoma progression and survival.”

Metastasis occurs when cancer cells escape the original tissue to establish new tumors elsewhere in the body.

Metastases lead to the majority of cancer deaths. Scientists have suspected that the ability to metastasize may be linked with gene mutations, but have yet to find a genetic change that could be proven to encourage metastasis.

Humans carry one of three different versions of APOE, designated APOE2, APOE3, and APOE4.

The gene products may vary by only one or two amino acids, but they show differential binding to and activation of APOE receptors, and represent major risk modifiers of some diseases, the authors wrote.

“Notably, the APOE4 variant is the largest monogenetic risk factor for Alzheimer’s disease, whereas APOE2 is protective. In addition, APOE variants modulate other inflammation-associated pathologies, including atherosclerosis.”

However, the scientists continued, “The potential association between APOE genotype and cancer outcome has remained inconclusive.”

Previous research in Tavazoie’s lab had linked APOE with the spread of melanoma.

The gene produces a protein that appears to interfere with a number of processes used by cancer cells to metastasize, such as forming blood vessels, growing deeper into healthy tissue, and holding off attack by tumor-fighting immune cells.

Benjamin Ostendorf, MD, a physician scientist in the lab, hypothesized that APOE variations could explain why melanoma progresses differently in different people.

The researchers carried out a series of experiments in melanoma-bearing mice that carried human variants of the APOE gene. The results showed that tumors in animals carrying APOE4 grew more slowly, and spread less than those in APOE2 variant mice.

A more detailed analysis indicated that APOE4 was the most effective version of APOE in terms of enhancing the immune response to tumor cells.

Compared to animals with other variants, the mice carrying APOE4 showed a greater abundance of tumor-fighting T cells recruited into the melanoma tumor, as well as reduced blood vessels.

“These data suggest that APOE genotype modulated both the abundance and the functional state of the tumor immune microenvironment, with the APOE4 variant eliciting an enhanced anti-tumor immune profile relative to the APOE2 variant,” the team wrote. “We think that a major impact of the variations in APOE arises from differences in how they modulate the immune system’s attack,” Ostendorf said.

Genetic data from more than 300 human melanoma patients mirrored the mouse experiments.

The researchers first looked at germline APOE variant status in melanoma patients in The Cancer Genome Atlas.

They found that APOE carrier status was significantly associated with survival.

“Strikingly, however, APOE carrier status was significantly associated with survival (median survival of 2.4, 5.2, and 10.1 years in APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, respectively,” they wrote.

The researchers then validated their findings in a different cohort of patients who were diagnosed with primary melanomas.

The combined results showed that on average people with APOE4 survived the longest, while those with APOE2 lived the shortest.

The findings suggest that it may be possible to look at melanoma patients’ genetics to assess the risk of their cancer progressing.

The findings could also influence the course of treatment. Additional studies in melanoma-bearing mice showed that APOE variant impacted the success of immunotherapy.

“APOE4 mice survived significantly longer than APOE2 mice upon anti-PD1 treatment, suggesting that APOE genotype modulates melanoma outcome, also in the context of immunotherapy,” the investigators wrote.

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