by Cora A. Hersh
There are almost 30,000 solid organ transplants performed each year in the United States. Transplantation is the treatment of choice for patients with end-stage organ failure, and while their life expectancy is extended, their risk for adverse health outcomes remains high. Although organ donors and recipients are matched on several factors before transplantation, there is no perfect match, apart from identical twins, resulting in a lifelong need for immunosuppressive medications. The drug cocktail used to prevent organ rejection results in a severely weakened immune system. In the immediate interval following transplantation and over the course of their lives, these individuals are at higher risk for many types of cancer, compared to the general population. Elevated risk is thought to arise from a combination of factors, such as persistent infection with carcinogenic viruses, chronic inflammation, coexisting medical conditions, and genotoxicity of the immunosuppression medications. By studying this population, epidemiologists can identify valuable clues about the role of the immune system in cancer etiology while helping clinicians and public health advisors develop screening and early detection approaches for these patients.
DCEG’s portfolio of research on cancer among solid organ transplant recipients is led by Eric Engels, M.D., M.P.H., a senior investigator in the Infections and Immunoepidemiology Branch (IIB), together with long-time collaborators Former Director Joseph F. Fraumeni, Jr., M.D.; Lindsay Morton, Ph.D., senior investigator in the Radiation Epidemiology Branch; and Ruth Pfeiffer, Ph.D., senior investigator in the Biostatistics Branch. As the transplant population in the U.S. swells, an effect of improvements in treatment and longer survival after transplantation, high cancer risk among recipients is an increasing public health concern.
To document the pattern of malignancies, Dr. Engels and his team have assembled the largest study of cancer among transplant recipients in the world. As of 2016, they have linked the U.S. transplant registry with 17 state and metropolitan area cancer registries, covering more than 280,000 individuals, approximately 45% of the nation’s organ recipients. Prior to this “big data” approach, many studies were based at single centers and relied on incomplete determination of cancers. Other linkage studies in Europe and Australia were much smaller (6,000-25,000 recipients), and some included only kidney recipients (the most commonly transplanted solid organ).
In 2011, the first paper using Transplant Cancer Match Study data confirmed earlier reports of a two-fold increase in cancer risk over the general population. In particular, Dr. Engels and colleagues showed that solid organ recipients in the U.S. experience a seven-fold increased risk of developing non-Hodgkin lymphoma, as well as elevated risk of 31 other individual types of cancer. In addition, the report refined risk estimates for recipients of specific transplanted organs.
The results gave insight into the etiology of certain cancers. For example, the team reported no increased risk of some of the most common cancers, such as breast, prostate, and ovarian cancers. This notable absence may indicate little or no role for immune system dysfunction in the development of these malignancies.
Following this initial investigation, Dr. Engels and his team went on to look more deeply into targeted subtopics, which have revealed further clues about cancer etiology as well as helped to direct screening guidelines. For instance, a study of cancer risk among patients with cystic fibrosis who received a lung transplant showed a 24-fold increased risk of colorectal cancer compared to the general population (in press at the Journal of Cystic Fibrosis). This greatly elevated risk probably reflects the effects of cystic fibrosis on the gastrointestinal tract, although an added effect of immunosuppression cannot be excluded. Notably, cystic fibrosis patients who received a lung transplant before age 50 had an absolute risk of developing colorectal cancer that was comparable to typical risk in the U.S. general population over age 50 (the age at which regular screening is recommended to begin). “This information regarding the very high risk of colorectal cancer at younger ages is being used to develop new guidelines for screening, which will probably start around age 30 for this special population,” says Dr. Engels.
Patients with end-stage renal disease (ESRD) can be treated with dialysis or kidney transplantation. Patients can spend months or years on dialysis while waiting for a suitable match. If they are successfully transplanted, they move to a period when they have a functioning kidney. The transplanted kidney may fail, returning them to non-function, dialysis, and waiting. This cycle can repeat numerous times. During periods of kidney nonfunction, the dose of immunosuppression medication is low. Once a functioning kidney is transplanted, the patient undergoes intensive immunosuppression to prevent rejection.
In an analysis of ESRD patients, Elizabeth Yanik, Ph.D., a postdoctoral fellow in IIB; Dr. Engels, and colleagues noticed a pattern of cancer risk associated with the cyclical nature of kidney function and non-function experienced by these individuals (Yanik, 2016). They observed a “sawtooth” pattern of risk of certain cancers, with sharp increases during intervals of kidney function (i.e., transplantation) and sharp decreases during kidney non-function (i.e., dialysis). This provided strong evidence of tight connections between immunosuppression and several infection- and immune-related cancers, such as non-Hodgkin lymphoma, lung cancer, and melanoma. There was an opposite pattern for kidney and thyroid cancers (i.e., higher risk during periods of dialysis, and a decline after transplantation), suggesting that the metabolic effects of kidney nonfunction, rather than immunosuppression, contribute to these cancers.
DCEG investigators have also examined the influence of particular medications on cancer risk. They noted elevated risk of several cancers associated with use of cyclosporine or azathioprine, two older immunosuppressive drugs that may directly increase DNA damage. In addition, transplant recipients often receive induction immunosuppressive therapy, which aims to prevent immediate organ rejection by drastically weakening the immune system. A team led by former IIB predoctoral fellow Hilary Robbins, M.S.P.H., noted an association between induction immunosuppression and risk of advanced-stage melanoma. These findings suggest intensive immunosuppression may have facilitated aggressive tumor behavior in undiagnosed, small melanomas present at the time of transplantation. Since melanomas can usually be detected with careful screening, these results highlight opportunities to catch melanomas at a stage when they can be removed.
Non-Hodgkin lymphoma, the most common cancer in transplant recipients, comprises many distinct disease subtypes. Of these, diffuse large B-cell lymphoma (DLBCL) is the most common; it is usually caused by loss of immune control of Epstein-Barr virus. Dr. Engels and colleagues examined the full spectrum of non-Hodgkin lymphoma subtypes in transplant recipients (Clarke, 2013), reporting excess risks for DLBCL and Burkitt lymphoma (also linked to Epstein-Barr virus), as well as rarer lymphoma subtypes. This pattern is the same in HIV-infected individuals, highlighting the importance of immunosuppression in the etiology of diverse lymphoma subtypes.
In another study, Dr. Engels and his team assessed risk of DLBCL in relation to human leukocyte antigen (HLA) patterns for organ donors and recipients. A mismatch in HLA proteins on the cell surface of donor tissue can signal to the immune system to attack the cell as “foreign.” There is enormous variability in HLA among humans, and although doctors try to match donors and recipients as closely as possible, some differences remain. When they compared donor and recipient HLA patterns and DLBCL in the recipient, the investigators found increased risk with increasing HLA mismatch. This result may reflect the need for higher doses of immunosuppressive medications in recipients with more HLA mismatch from their donors, or it could suggest that chronic immune stimulation from the donor organ contributes as an etiologic factor for DLBCL.
“Having an abnormal immune system probably predisposes a lot of people to develop different cancers, so what we’ve discovered so far could be just the tip of the iceberg.”
As noted above, findings from the Transplant Cancer Match Study are already being used to revise cancer screening guidelines for transplant recipients. The incidence data and paired medical records also point the way toward deeper investigations: “We take what we learn from database analyses and conduct molecular epidemiologic studies to understand the biological mechanisms that underlie those associations,” said Dr. Engels. “For example, we have been working with other transplant researchers to assess whether markers of immune stimulation are predictive of developing lymphoma.”
Patterns of cancer incidence may change as treatment improves and the lifespan of immunosuppressed people increases. “We’re just now getting to understand the interplay between aging and immunosuppression in cancer risk,” said Dr. Engels. Future research may also explore the pattern of cancer risk among people with more moderate cases of immune dysfunction. Their risk factors are less dramatic and may be harder to study, but the findings could be relevant to a greater percentage of the population. As Dr. Engels notes, “having an abnormal immune system probably predisposes a lot of people to develop different cancers, so what we’ve discovered so far could be just the tip of the iceberg.”
Engels EA et al. Spectrum of cancer risk among U.S. solid organ transplant recipients. JAMA 2011.
Engels EA et al. Cancer risk among lung transplant recipients with cystic fibrosis. J Cyst Fibros 2016.
Yanik EL et al. Variation in Cancer Incidence among Patients with ESRD during Kidney Function and Nonfunction Intervals. J Am Soc Nephrol 2016.
Clarke CA et al. Risk of lymphoma subtypes after solid organ transplantation in the United States. Br J Cancer 2013.