First Study Published on How Inherited Genetic Changes Affect the Spread of Cancer

Although inherited gene variants / changes are known to be associated with metastasis in cancer, which genetic changes have an effect had not yet been clarified. A study published on 25 May 2020 in Nature found that APOE (apolipoprotein E) gene variants affect cancer metastasis and development in different ways. Human and animal studies found that the APOE4 gene variant slowed the spread of melanoma and enhanced the immune system response against melanoma.

Most deaths from cancer result from metastasis. Metastasis is the migration of cancer cells to different tissues and organs. The presence of metastasis-associated gene mutations had not been identified until now. The study focused on the APOE gene. People carry one of 3 versions of the APOE gene (APOE2, APOE3 and APOE4). The proteins produced by these genes show certain differences. For example, they differ in their ability to bind to and activate APOE receptors. This plays a role in the development of certain diseases. In Alzheimer's disease, the APOE4 gene variant poses a risk, while the APOE2 gene has a protective effect. APOE gene variants also play a role in atherosclerosis and other inflammation-related diseases. However, the relationship between APOE gene variants and cancer is still unknown. This study examined the effects of APOE gene variants in melanoma.

Analyses in Mice with Melanoma Carrying Variants of the Human APOE Gene Found That

• Tumors in mice carrying the APOE4 gene variant grew more slowly and spread less than tumors in mice carrying the APOE2 gene variant.
• The APOE4 gene variant was found to support the immune response against tumors.
• Mice carrying the APOE4 gene were found to have more T cells attacking tumors. Fewer blood vessels were also observed in melanoma tumors in these mice.
• The APOE4 gene variant was found to affect the tumor microenvironment in ways that support the immune system. In addition, genetic data from 300 melanoma patients were analyzed.

Analysis of Inherited APOE Gene Variant Status and Survival in the Cancer Genome Atlas Found That

• The APOE gene variant was found to be significantly associated with survival. Median survival was 10.1 years in carriers of the APOE4 gene variant, 5.2 years for APOE3 and 2.4 years for APOE2.
• These findings were subsequently confirmed in different groups of patients diagnosed with melanoma. Patients carrying the APOE4 gene variant were found to have longer survival than those carrying the APOE2 gene variant. Survival was very short in patients with the APOE2 gene variant.
• APOE gene variants were also found to affect the response to immunotherapy. Mice carrying the APOE4 gene variant lived longer after Anti-PD1 treatment.
• Analyses were also performed in melanoma patients who developed progression after Anti CTLA4 treatment and received anti-PD1 treatment. Survival was found to be longest in patients carrying the APOE4 gene variant. Patients with the shortest survival carried the APOE2 gene variant.
• Finally, the effect of increasing APOE protein production through medication in melanoma was examined. APOE4 production was increased with the experimental drug RGX-104. The APOE4 gene variant, increased through APOE production, enabled a successful immune response against tumors. RGX-104 is currently being tested in clinical trials.

What Does This Study Mean for Us?

• The first study presenting evidence that inherited gene variants affect metastasis has now been published.
• The APOE4 gene variant was found to play a role in developing an immune response against melanoma. Patients with the APOE4 gene variant were found to have longer survival.
• Inherited gene variants may help in planning treatment and predicting the course of disease in melanoma patients.
• These findings need to be confirmed in prospective clinical trials with large numbers of participants. The role of APOE genotype differences in different cancer types should also be investigated.
• Further research should determine how best to plan treatment for patients with APOE gene variants (types).