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James J. Goedert, M.D.

Senior Investigator

James J. Goedert, M.D.

James J. Goedert, M.D.

Organization:National Cancer Institute
Division of Cancer Epidemiology & Genetics, Infections and Immunoepidemiology Branch
Address:NCI Shady Grove
Room 6E106
Phone:240-276-7103
E-mail:goedertj@mail.nih.gov

Biography

Dr. Goedert earned a B.A. degree in psychology from Yale University and an M.D. from Loyola University Stritch School of Medicine. He received postgraduate training at Georgetown University Hospital, and he is board certified in internal medicine and medical oncology. Dr. Goedert joined the NCI Epidemiology and Biostatistics Program as a medical staff fellow in 1980. He was appointed chief of the AIDS and Cancer Section of the Viral Epidemiology Branch in 1992, and served as chief of the Branch from 1995 to 2008. Dr. Goedert received the PHS Outstanding Service Medal and the International AIDS Society's 1992 International LIFE Prize for his study of twins born to HIV-1-infected mothers. He was elected chair of the NCI Faculty of HIV and Cancer Associated Viruses in 2001, and he serves on the NCI Special Studies Institutional Review Board and on the editorial boards of several journals.

Research Interests

The epidemiology of infection-associated malignancies provides the scientific underpinnings for large-scale, effective public health and clinical interventions. It also affords opportunities for insight on basic mechanisms of carcinogenesis.

The human microbiome and cancer

The microbiome refers to the sum of all of the gene sequences in a community of microbes. Rapidly improving, high-throughput DNA amplification and sequencing technologies are being used to characterize the microbial communities that reside on and in the human body, as well as their associations with disease. Our goal is to establish a bank of fecal specimens, suitable for microbiome and other assays, prospectively and cost-effectively collected from a general population of many thousands with essential covariate data and good ascertainment of cancer events. Toward that goal, we are pursuing a two-pronged strategy.
 

We have made the most progress on the first strategy, which aims to identify associations of fecal microbiome metrics with malignancies and with cancer risk factors. Colorectal cancer (CRC) is a major focus. In a case-control study using data and specimens previously collected by other DCEG researchers, we found that CRC cases had reduced fecal microbiome alpha diversity, increased carriage of Fusobacterium and Porphyromonas taxa, and reduced abundance of Clostridia taxa. Metabolomic analysis of the same specimens revealed 41 small molecules that differed between cases and controls, providing potential for improved diagnostic methods and new insights on carcinogenesis. Metagenome analyses of associations with CRC and with fecal metabolites are in progress. Our study of twins, with collaborators at Washington University in St. Louis and the University of Southern California, found that 13 Hodgkin lymphoma survivors had less fecal microbiome diversity compared to their unaffected co-twin controls. Such reduced diversity could be a consequence of several things, including the lymphoma, its treatment, or even a propensity for Hodgkin lymphoma as postulated by the “hygiene hypothesis”.
 

Our first strategy has also focused on endogenous estrogens and postmenopausal breast cancer. In 51 epidemiologists recruited from DCEG, our collaboration with the University of Maryland Medical School Institute of Genome Sciences (IGS) revealed that fecal microbiome alpha diversity was significantly lower with younger age, use of various prescription medications, and, in men and postmenopausal women, lower levels of systemic estrogens. The estrogen association is being pursued with fecal metagenome and meta-transcriptome analyses, and in a detailed study of postmenopausal women, including a recently completed case-control study of newly diagnosed breast cancer in collaboration with IGS and Kaiser Permanente Colorado.
 

The second strategy is to identify and resolve problems with obtaining microbiome-quality feces from existing cohorts, prepaid health plans, or populations that are being screened for CRC. Our study of DCEG epidemiologists demonstrated excellent reproducibility of microbiome alpha and beta diversity metrics in stool samples that were self-collected by the participants using two devices containing RNAlater. In the same population we are evaluating whether used fecal immunochemical test (FIT) devices yield equivalent microbiome reproducibility. Feasibility of collecting and performing fecal microbiome analyses in a large cohort in Shanghai has been demonstrated in a study of 68 participants in a CRC screening program in collaboration with the Shanghai Center for Disease Control and BGI.  

HIV/AIDS and breast cancer

Using data from the HIV AIDS Cancer Match (HACM), we showed that HIV-infected women in the U.S. had a highly significant deficit in breast cancer risk during the 1980s, which attenuated with improving availability and efficacy of ART during the 1990s and early 2000s. The breast cancer deficit was unrelated to CD4 count and other measures of immunity. In collaboration with prospective cohort studies of HIV-infected women in the U.S., we found that those who developed breast cancer were 80-90% less likely than control women to have HIV with tropism for the CXCR4 chemokine co-receptor, as determined with a viral phenotyping assay. In the same population, we subsequently showed that Sanger sequencing of HIV DNA – a cheaper, more cost-effective alternative to phenotyping – yielded the same 80-90% lower risk of breast cancer for women with CXCR4-using HIV infection. These findings are consistent with in vitro evidence that signaling of CXCR4 induces apoptosis of breast cancer cells. Additionally, these results suggest that CXCR4 could be an effective pharmacologic or immunologic target to reduce breast cancer for women in the general population.

Classical Kaposi sarcoma (KS) and KS-associated herpes virus (KSHV)

The primary cause of KS is infection with KSHV, otherwise known as human herpesvirus 8. AIDS KS has become the most common of all malignancies in areas of sub-Saharan Africa with a high prevalence of both HIV and KSHV. In contrast, classical (non-AIDS) KS is rare, even in elderly Mediterranean populations that have KSHV seroprevalence above 10 percent. In case-control studies in Italy, we found that risk of cKS was significantly associated with  use of corticosteroid medications and especially with non-smoking. Null results in our randomized clinical trial of topical nicotine to treat cKS suggested that other, perhaps inflammation-related consequences of smoking may reduce cKS risk. We found that cKS was associated with polymorphisms in several immune-response genes, with deficient in vitro responses to KSHV peptides, and with deficient delayed-type hypersensitivity responses in the legs, where cKS usually originates. We recently found that cKS was associated with elevated plasma levels of  four of 70 immunity markers – soluble interleukin (sIL)-1 receptor II, sIL-2 receptor alpha, CC-chemokine ligand 3 (also known as MIP-1α), and especially CXC-chemokine ligand 10 (CXCL-10, also known as IP-10), which has been a focus of AIDS-KS treatment trials.  Analyses of HLA associations with cKS and with KSHV seropositivity are in progress.

Information for Journalists

To request an interview with a DCEG investigator, contact the NCI Office of Media Relations:

E-mail:
ncipressofficers@
mail.nih.gov

Phone: 301-496-6641