Patients with the skin cancer melanoma who have inherited a specific variant of the cholesterol carrying gene APOE, which is associated with increased risk for Alzheimer’s and other diseases, have increased survival compared with people who have inherited other variants of this gene.
The research, which was published in the journal Nature Medicine, showed that both mouse and human carriers of the APOE4 gene variant had less melanoma progression and metastasis compared with those who had the APOE2 gene variant, as well as a better response to cancer immunotherapy.
“Patients often ask ‘Why am I so unlucky? Why did my cancer spread?’ As doctors, we never had an answer,” commented lead investigator and author Sohail Tavazoie, MD, PhD, a professor at the Rockefeller University, USA. “This research provides an explanation.”
There are three variants of the APOE gene. The APOE4 gene variant is carried by 13.7% of the world’s population and is associated with increased risk for a number of different diseases including Alzheimer’s and atherosclerosis, poor outlook in multiple sclerosis and other diseases including infection with Covid-19, and reduced life span.
APOE2 in contrast, carried by 8.4% of the world’s population, has not previously been linked with significant disease risk, excepting some forms of cardiovascular disease. Finally, APOE3, which is the most common variant carried by 77.9% of people globally, is considered ‘neutral’ and not linked with disease risk.
Tavazoie and co-authors looked at the APOE variant status in patients from the Cancer Genome Atlas. They found that while the APOE gene did not appear to impact risk for developing melanoma, it did impact progression and survival from the disease. They found that patients with melanoma who had the APOE4 variant had a median survival of 10.1 years compared with 5.2 and 2.4 years in APOE3 and APOE2 carriers, respectively.
The researchers also looked at mouse models carrying APOE variants to assess melanoma risk. They found that mice expressing the human APOE4 variant had less cancer progression and metastasis than APOE2 mice. On a cellular level, they found that APOE4 mice had a greater anti-cancer immune response than those with other gene variants.
Both mice and humans with the APOE4 variant also had better response to treatment with cancer immunotherapy drugs. Mice with this variant had a better response to PD1 checkpoint inhibitors versus APOE2 mice. Similarly, patients with the APOE4 variant had improved survival after treatment with PD1 checkpoint inhibitors after failed treatment with other drugs.
In addition to his academic role, Tavazoie is a co-founder of the biotech company Rgenix. The company has developed a candidate drug that can increase production of APOE protein. The researchers tested this candidate drug in the mouse models and found that it helped mice with the APOE4 gene variant to suppress tumor growth, but not the mice with other variants.
The researchers hope their findings can help guide cancer treatment and help predict prognosis for patients in the future. “We need to find those patients whose genetics put them at risk for poor survival and determine what therapies work best for them,” Tavazoie commented.
They also want to investigate if APOE status affects other cancers in addition to melanoma and find out more about the links with Alzheimer’s disease.