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.

When researchers analyzed the immune cells in the tumors and grouped them by type, they found more cancer-fighting cells in mice with ApoE4. [Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology at The Rockefeller University]

“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.

Analysis of data on human melanoma patients who had received anti-PD1 checkpoint inhibition after progression on anti-CTLA4 therapy similarly suggested better response to therapy among individuals with the APOE4 variant. “APOE4 and APOE2 carriers in this study also exhibited the longest and shortest survival outcomes, respectively,” the scientists stated.

In a final set of experiments, the team investigated whether pharmacologically boosting APOE production could impact on melanoma survival. They showed that the experimental compound RGX-104, which increases production of APOE, helped APOE4 variant to fight off tumors. Tavazoie is a scientific co-founder of Rgenix, the company that developed RGX-104, which is currently in clinical trials.

“Our work provides causal evidence that, in a reversal of their role in neurodegenerative diseases, the highly prevalent APOE4 and APOE2 variants confer favorable and poor progression outcomes in melanoma, respectively, by affecting anti-tumor immunity,” the scientists concluded. “Our findings have several potential clinical implications. Most importantly, they suggest that common germline variants might serve as biomarkers to identify patients with melanoma who are at high risk for metastatic relapse and melanoma-associated death for treatment with adjuvant systemic therapy.”

The team acknowledged that their findings will need to be replicated in prospective studies. It will also be important to assess the effect of APOE genotype on the outcome of different types of cancer, they noted. “More generally, our findings support the notion that hereditary germline variants in the same gene can positively or negatively affect future progression and survival outcomes and responsiveness to therapy in a common human malignancy.”

Further research will be needed to determine how to optimize treatments for patients with other APOE variants, Tavazoie suggested. APOE2, for instance, was associated with an increased risk of metastasis, whereas their evidence to date suggested that the ability of APOE3 to suppress metastasis falls between that of the other two variants. “We need to find those patients whose genetics put them at risk for poor survival and determine what therapies work best for them,” Tavazoie said.

The implications may extend beyond cancer, the authors suggested. For example, in contrast with its apparent suppression of cancer progression, APOE4 has been linked with increased risk of Alzheimer’s disease. “It’s not quite clear what APOE does in Alzheimer’s, but we believe our work in cancer can inform our understanding of this disease as well,” Tavazoie said. His lab, normally focused on cancer, has begun investigating the connection to the neurodegenerative disorder.

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