Patients with cancer who are living with the human immunodeficiency virus (HIV) infection had an increased epigenetic age compared with patients with cancer living without the HIV infection, according to a new study presented by Coghill et al at the American Association for Cancer Research (AACR) Special Conference: Aging and Cancer (Abstract B012).
Background
Researchers have discovered that as a result of the wider use of antiretroviral therapy, patients who are HIV-positive are living longer, making them more susceptible to cancer and other age-related diseases.
“Unfortunately, clinical outcomes after a cancer diagnosis in patients with HIV infection are poorer compared to patients without HIV [infection],” explained lead study author Anna Coghill, PhD, MPH, a researcher in the Department of Cancer Epidemiology at the Moffitt Cancer Center. “An important focus of the field is identifying molecular features that could explain the poorer treatment responses in patients with HIV [infection].”
Dr. Coghill and her colleagues hypothesized that patients who are HIV-positive may have differences in their epigenetic ages compared with those who are HIV-negative. “When we think of a person’s age, we typically think of their chronological age—how many years they have been alive. An alternative metric is epigenetic age, which is based on patterns of methylation that accumulate on DNA over time,” Dr. Coghill highlighted. “Patients with HIV [infection] may have DNA that appears older than their chronologic age.”
This could be the result of the long-term immune activation, inflammation, and metabolic changes that HIV infection causes, she added.
KEY POINTS
- Epigenetic age was significantly higher in patients who were HIV-positive compared with patients who were HIV-negative; by the GrimAge algorithm, patients who were HIV-positive had an average biological age that was 4.5 years older.
- Patients who were HIV-positive also had cell division rates that were 70% higher than patients who were HIV-negative, as determined by the epiTOC2 algorithm.
- The tumors of patients who were HIV-positive were found to have significantly lower proportions of certain immune cells—including neutrophils and CD4-positive T cells—as well as significantly higher proportions of others, such as memory B cells and memory CD8-positive T cells.
Study Methods and Findings
In this study, Dr. Coghill and her colleagues compared the epigenetic ages of 65 patients with non–acquired immunodeficiency syndrome (AIDS)-defining solid tumors who were HIV-positive with those of matched patients who had similar tumor types, treatment statuses, and chronologic ages, but were HIV-negative. The researchers performed DNA methylation sequencing on the patients’ tumor samples—which were then translated to epigenetic ages with the use of two distinct algorithms: epigenetic timer of cancer-2 (epiTOC2) and the epigenetic clock GrimAge. DNA methylation data were also used to measure the proportion of immune cells in the tumor, since immune cell proportions are known to be affected by HIV infection.
The researchers discovered that epigenetic age was significantly higher in patients who were HIV-positive compared with patients who were HIV-negative; by the GrimAge algorithm, patients who were HIV-positive had an average biological age that was 4.5 years older. Patients who were HIV-positive also had cell division rates that were 70% higher than patients who were HIV-negative, as determined by the epiTOC2 algorithm.
In addition, the tumors of patients who were HIV-positive were found to have significantly lower proportions of certain immune cells—including neutrophils and CD4-positive T cells—as well as significantly higher proportions of others, such as memory B cells and memory CD8-positive T cells. Epigenetic age as determined by the GrimAge algorithm remained higher among patients who were HIV-positive even after adjusting for differences in immune cell composition—an important result given that the GrimAge algorithm has been linked to mortality risk in other studies.
Conclusions
The researchers further noted that changes to DNA methylation, such as those identified in patients who were HIV-positive, could promote cancer by affecting gene expression—although additional research is needed to determine the correlation.
“Our results show that patients with HIV [infection] may be biologically older than those without HIV [infection], which could impact how their tumors respond to treatment,” concluded Dr. Coghill, adding that ongoing studies from her group are aiming to understand how differences in epigenetic age impact clinical outcomes. “We hope that understanding why patients with HIV [infection] have worse outcomes to cancer therapy will serve as an initial step towards reducing this disparity.”
Disclosure: The research in this study was supported by the National Cancer Institute of the National Institutes of Health.
