Genetic Variant May Increase Risk of HIV-Related NHL

NEW ORLEANS—A genetic variant has been found to double an HIV-infected individuals’ risk of developing non-Hodgkin’s lymphoma (NHL). Charles S. Rabkin, MD, HIV/Cancer Coordinator, Viral Epidemiology Branch, National Cancer Institute, presented the report at the 92^nd Annual Meeting of the American Association for Cancer Research (AACR).

Dr. Rabkin and his colleagues tested HIV-infected persons for a variant in the gene for interleukin-6 (IL-6), which is important in the control of the immune system and in tumor growth. They found that patients with the IL-6-174C variant in the IL-6 promoter region, which decreases IL-6 production, were at twice the risk of developing NHL.

The finding may explain why HIV-infected whites are more likely to develop NHL than HIV-infected blacks, since the mutation is five times more common in whites, he said.

NHL occurs annually in 1% to 2% of untreated patients with advanced HIV infection, as does Kaposi’s sarcoma. But Kaposi’s sarcoma has mostly disappeared in the era of highly active antiretroviral therapy. The risk of NHL, however, persists and represents an increasingly important complication of HIV infection, Dr. Rabkin said.

In the HIV-infected person, NHL arises as a late complication in the setting of advanced immunodeficiency. The mechanisms by which immune dysregulation leads to B-cell lymphoma are poorly understood, but may relate to disruption of cytokine control and chronic B-cell hyperactivation. Lymphomas may arise through a multistage process progressing from generalized growth of stimulated B-cells to expansion of certain antigen-specific clones to subsequent outgrowth of a monoclonal tumor.

The study data came from an analysis of the AIDS-Cancer Cohort Study, a case-control study of AIDS-related NHL, Kaposi’s sarcoma, and other malignancies in approximately 2,500 subjects with advanced HIV infection.

The researchers hypothesized that an inherited genetic variation of cytokine genes is associated with an increased risk of NHL. The candidates were six genes that regulate the immune response to infection. A common polymorphism in the IL-6 promoter region (IL-6-174C) was found to decrease transcription in vitro and plasma IL-6 levels in vivo.

More than 1,700 individuals with advanced HIV infection were tested for the IL-6-174C variant and followed for 2 years; 34 individuals had NHL or developed it during follow-up. The results showed that carriers of the variant were twice as likely to develop NHL as non-carriers. IL-6-174C carriers also had an increased prevalence and incidence of HIV dementia, cytomegalovirus disease, and Pneumocystis carinii pneumonia.

The gene mutation was not associated with the development of Kaposi’s sarcoma, Dr. Rabkin reported. He said that this makes sense because Kaposi’s sarcoma develops early in the course of HIV infection and is due to stimulation of the immune system. He concluded that IL-6 may be a favorable anti-inflammatory response to HIV immune disruption, and relative IL-6 deficiency may predispose to B-cell transformation to cancer.

The finding of a genetic basis for susceptibility to NHL may have implications in other malignant states, Dr. Rabkin said. "AIDS-associated malignancy represents a model system for investigations of carcinogenesis. There are few human conditions in which cancer rates are of the magnitude of HIV infection," he said.

A follow-up study is planned to examine whether non-HIV-infected patients with NHL are more likely to carry the same genetic variant.