Photo by Todd McNaught.
A triple-divisional study may help explain why only a small proportion of women infected with the cancer-causing form of the human papillomavirus (HPV) later develop cervical cancer.
By analyzing immune-system genes - known as human leukocyte antigen (HLA) genes - of women with and without cervical cancer, researchers in the Public Health Sciences, Clinical Research and Human Biology Divisions found evidence that certain gene variants may affect women's cancer risk.
The findings, which confirm and extend observations made in other populations, could ultimately aid scientists as they continue to develop vaccines to treat cancer in women already infected with HPV.
Dr. Margaret Madeleine, an epidemiologist and senior staff scientist in PHS, is senior author of the study, which appears in the Dec. 1 edition of the Journal of Infectious Diseases.
Different HPV subtypes have been found to cause common warts, genital warts and cervical cancer, the second most common cancer among women. Yet despite the strong association between HPV infection and cancer, Madeleine said only a small percentage of women infected by the virus eventually develop cancer.
"It appears that the immune system's ability to detect and clear HPV from the body is a pivotal step on the pathway to cancer," she said. "For example, immunocompromised patients, including renal (kidney) transplant patients and AIDS patients, are at an increased of HPV-related cancers.
"When we think about risk factors that determine susceptibility, there are three pieces to the puzzle: the host, the virus, and the environment. We look at each puzzle piece individually, and then look at how the different pieces fit together on the pathway to disease.
"There may be genetic components of the immune system that affect disease susceptibility, such as HLA, that are modified by environmental factors such as smoking or hormones or by viral variants."
The researchers examined the DNA from blood specimens from 315 women with invasive, squamous-cell cervical cancer and 381 women without cancer to determine the precise genetic composition of a subset of their HLA genes known as Class II HLA genes. Women with cancer were identified through PHS' Cancer Surveillance System, a registry that collects information on cancer incidence in Western Washington.
"This study is the kind of project that we are uniquely able to do because of the large number of cases we have accrued through the HPV Program Project, an interdisciplinary effort in its 15th year,"Madeleine said.
McDougall leads the project, which builds on the population-based case-control studies of HPV-related cancers that Dr. Janet Daling initiated in 1978.
Using sensitive DNA-typing methods similar to those used for tissue-type matching leukemia patients with appropriate stem-cell donors, the researchers identified gene variants that may affect an HPV-infected woman's cervical cancer risk.
DNA analysis was conducted at the Seattle Cancer Care Alliance's Immunogenetics Laboratory, which routinely analyzes HLA genes of patients preparing to undergo bone-marrow or stem-cell transplants and potential donors to identify pairs with compatible tissue types.
HLA genes contain the blueprints for proteins that sit on the surfaces of all cells in the body. These proteins provide a molecular identification badge that lets the immune system distinguish "self"from "non-self."This is the basis for the body's ability to react to and destroy foreign cells, such as pathogenic bacteria and viruses or incompatible transplanted tissues.
HLA proteins work by latching on to pieces of a virus or other foreign tissue and displaying the bits to the immune system to trigger a protective response. Presumably, different variants of HLA molecules display foreign matter in different ways, eliciting stronger or weaker immune responses in their hosts.
"Because of the Immunogenetics Lab, we could conduct high-resolution HLA typing," Madeleine said. "Use of this technology, in conjunction with the large number of subjects available for analysis, thanks to the extensive HPV research effort at the center, let us determine that certain HLA variants may substantially affect susceptibility."
Specifically, researchers identified variants or combinations of variants (called haplotypes) that were associated with two-and-a-half times higher cancer risk, as well as other variants that appear to cut a woman's cancer risk by more than a third.
Madeleine said that the findings could have clinical applications, particularly for vaccine development.
"A vaccine to prevent HPV infection is almost up and running, and our research won't impact that," she said. "But a therapeutic vaccine is being developed for women already infected with the virus, and HLA type may be an important factor for creating an effective therapeutic vaccine."
The group has already begun the next phase of the project, part of which is to examine a different subset of HLA genes known as Class I genes.
In addition, Madeleine said, future studies of HLA genes and cervical cancer will compare the risk of cancer associated with the two major cancer-causing HPV types (HPV16 and HPV18) and specific HLA variants or variant combinations.
Who wrote the HPV study?
Besides Dr. Margaret Madeleine, study co-authors included Kara Cushing-Haugen and Dr. Babette Brumback, biostatisticians at the center and the University of Washington, respectively; Drs. Stephen Schwartz and Janet Daling, epidemiologists in PHS; Dr. Lee Nelson, Clinical Research Division; Anajane Smith, manager of the Alliance Immunogenetics lab; and Katherine Shera and Drs. Peggy Porter, James McDougall and Denise Galloway of Human Biology and PHS.
Galloway leads the HLA study as part of her work to understand the viral and immune-system factors associated with HPV-related cancers.