Biography

Dr. Hildesheim received a Ph.D. in epidemiology from The Johns Hopkins School of Hygiene and Public Health in 1991. He joined the NCI in 1987, and became Chief of the Infections and Immunoepidemiology Branch in 2008. Dr. Hildesheim's research focuses on host and viral factors involved in the pathogenesis of DNA virus-related tumors, with a particular emphasis on host immunological factors linked to human papillomavirus (HPV) and Epstein-Barr virus (EBV)-related tumors. He is a recipient of the NIH Fellows Award for Research Excellence.

Research Interests

We are conducting large-scale studies to investigate exogenous and host factors involved in the pathogenesis of DNA virus-related tumors. Two groups of tumors are under investigation: female gynecological cancers linked to HPV and nasopharyngeal cancer linked to EBV. Non-viral factors involved in the pathogenesis of HPV and EBV-related cancers are also being examined, since infection alone is rarely sufficient for the development of cancer.

Cervical Cancer

Our previous studies suggested that in addition to HPV infection, important determinants of cervical disease progression may include host immune response to HPV; exogenous and behavioral factors, such as parity and oral contraceptive use; and infection with sexually transmitted agents other than HPV. To further define the factors related to the progression of low?grade squamous intraepithelial lesions (LSIL), large cohort studies are being conducted in Costa Rica and in the United States. The Costa Rica cohort is a population-based study of 10,000 women, which is in its seventh and final year of follow-up. As part of this study, women with evidence of HPV infection, with or without LSIL, and a sample of the remaining cohort are being followed every six months to one year with repeat cytological screening, biological specimen collection, and assessment of risk factor profiles. Specific factors being evaluated include mucosal immune response, HLA alleles, chromosomal alterations, contraceptive and reproductive practices, diet, cigarette smoking, and infection with sexually transmitted agents other than HPV.

The U.S.-based study, in which women are being seen at four clinical centers, is aimed at investigating specific immune responses to viral infection and risk of subsequent persistenceand/or progression of lesions. In this study, close to 1,000 women diagnosed with LSIL are being followed with repeat Pap smears, specimen collection, and risk factor assessment every six months for a period of two years. Biological samples are being tested for cellular and humoral responses to HPV to assess various immunological markers that may correlate with disease status over time.

We have recently begun to determine the efficacy of two prophylactic HPV vaccines. Phase I and II safety and immunogenicity trials were conducted in the United States, and a large efficacy Phase III trial is now underway in Costa Rica.

Nasopharyngeal Cancer

Nasopharyngeal cancer has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasians. While infection with EBV is believed to be necessary for development of the cancer, both genetic and exogenous factors are also thought to be important. To investigate the role of genetic, dietary, occupational, and behavioral factors in the etiology of nasopharyngeal cancer, a case-control study was conducted in Taiwan. Analyses thus far suggest an association between risk and specific variants of the enzyme CYP2E1, HLA type, smoking, and dietary micronutrients. Other dietary and occupational factors are being evaluated, including consumption of nitrates, nitrites, and nitrosamines; and occupational exposure to formaldehyde, solvents, wood dusts, and nitrosamines. A large-scale linkage study is underway in Taiwan to assess systematically the genetic and environmental determinants of nasopharyngeal cancer.

Keywords

cervical cancer, human papillomaviruses, immune response, vaccines, nasopharyngeal cancer, DNA tumor viruses, genetic susceptibility

Selected Publications

• Hildesheim A, et al. "p53 polymorphism and risk of cervical cancer." Nature 1998; 396:531-532. Hildesheim A, et al. "Cytokine and immunoglobulin concentrations in cervical secretions: reproducibility of the Weck-cel collection instrument and correlates of immune measures." J Immunol Meth 1999; 225:131-143.
• Herrero R, et al. "Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica." J Natl Cancer Inst 2000; 92:464-474.
• Hildesheim A, et al. "HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica." Br J Cancer 2001; 84: 1219-1226.

Collaborators

DCEG Collaborators

• Philip Castle, Ph.D.; Alisa Goldstein, Ph.D.; James Lacey, Ph.D.; Mark Schiffman, M.D.; Sholom Wacholder, Ph.D.; Sophia Wang, Ph.D.; Mary Ward, Ph.D., Mark Sherman, M.D.

Other NCI Collaborators

• Lucy Anderson, Ph.D.; Jay Berzofsky, M.D.; Kenneth Buetow, Ph.D.; Doug Lowy, M.D.; Lisa McShane, Ph.D.; John Schiller, Ph.D.; Diane Solomon, M.D.

Other NIH Collaborators

• Scott Diehl, Ph.D., National Institute of Dental and Craniofacial Research

Other Scientific Collaborators

• Raymond Apple, Ph.D., Roche Molecular Systems, Alameda, CA
• Michael Basseler, Ph.D.; Mary Carrington, Ph.D., Science Applications International Corporation-Frederick, Frederick, MD
• Concepcion Bratti, M.D.; Rolando Herrero, M.D., Ministry of Health, San Jose, Costa Rica
• Robert Burk, M.D., Albert Einstein College of Medicine, Bronx, NY
• Chien-Jen Chen, Ph.D., National Taiwan University, Taipei, Taiwan
• Peggy Crowley-Nowick, Harvard Medical School, Boston, MA
• Clayton Harro, M.D., Johns Hopkins University, Baltimore, MD
• Robert Kurman, M.D. The Johns Hopkins University School of Medicine, Baltimore, MD
• Ana Cecilia Rodriguez, M.D., Costa Rican Social Security Administration, San Jose, Costa Rica
• Keerti Shah, M.D., Dr.P.H., The Johns Hopkins School of Hygiene and Public Health, Baltimore, MD
• Patti Gravitt, M.S. Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health Baltimore, MD