Biography

Dr. McGlynn received an M.P.H. in population studies from Tulane University and a Ph.D. in epidemiology from the University of Pennsylvania. She conducted postdoctoral research at Fox Chase Cancer Center in Philadelphia, PA, where she subsequently received a faculty appointment. Dr. McGlynn joined the Environmental Epidemiology Branch in 1998. She holds an adjunct appointment in the Department of Medicine and the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania.

Research Interests

Molecular Epidemiology of Testicular and Liver Cancers

The incidence of testicular cancer and primary liver cancer are increasing in many populations, although there is wide geographic and ethnic variability in their rates. The reasons for the increases are unclear. We are using a variety a study designs to investigate risk factors that may contribute to the increasing rates, including the role of genetic susceptibility.

Testicular Cancer

Testicular cancer is the most common malignancy among U.S. men in the 25 to 45-year-old age group. Its etiology, however, is poorly understood. The only well described risk factors are cryptorchism and a personal or family history of testicular cancer. We are initiating a large case-control study of testicular cancer to examine a wide variety of endogenous and exogenous risk factors. Of particular interest are organochlorine exposures, endogenous hormone levels, viral exposures, prenatal milieu, and genetic susceptibility.

Although it has been argued that organochlorine exposures may be related to the development of testicular cancer, the hypothesis has never been tested. A new case-control study conducted among members of the U.S. Armed Forces for whom pre-diagnostic sera are available will permit us to examine the effect of organochlorines and to determine whether genetic susceptibility influences the development of testicular cancer in organochlorine-exposed individuals. The effect of hormones on testicular cancer risk has been difficult to investigate because of the retrospective nature of most studies. In general, however, case-control studies reported that men with testicular cancer have higher follicle stimulating hormone levels and somewhat lower testosterone levels than controls. These observations suggest that testicular cancer arises in a state of "gonadotropin overdrive" in which the gonads have lost the ability to respond to gonadotropins. Our study will test this hypothesis by examining gonadotropin levels in pre-diagnostic sera to determine whether higher levels are also seen prior to cancer diagnosis.

An infectious etiology of testicular cancer has been suggested based on epidemiologic similarities with Hodgkin's disease. While a number of studies have examined viral antibody titres in affected men, few have had adequate power to test an association with testicular cancer. The most promising candidate viruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), are members of the herpes family, and are known to cause p53 overexpression, a common finding in testicular cancer. In addition, both viruses have oncogenic potential, and CMV infection during pregnancy has been associated with cryptorchism in the newborn. Recently, the DNA of parvovirus B19, a member of the parvoviridae family, was found in testicular germ cell tumors. Antibody titres of CMV, EBV, and parvovirus B19 will be assessed among the case-control study participants. If any virus appears to be related to case status, the viral sequences in the tumor tissue will be examined.

The suggestion that testicular cancer may be associated with both hormonal aberrations and environmental endocrine modulators indicates that risk may be affected by genetic variability in loci related to hormonal and organochlorine metabolism. Given the early onset age of testicular cancer and its association with congenital anomalies, our study will examine risk factors related to the perinatal milieu. Information will be collected from mothers and sons on a variety of factors, including congenital anomalies such as hypospadias, inguinal hernia, hydrocele, and testicular atrophy; prematurity; birth weight; birth order; sibship size; neonatal jaundice; singleton/twin status; and chromosomal aberrations. Maternal factors that will be evaluated include childbirth age, bleeding during pregnancy, degree of nausea during pregnancy, hormonal use (including DES) during pregnancy, body weight, and socioeconomic status.

Primary Liver Cancer

In most high-risk areas of the world, such as east Asia and sub-Saharan Africa, chronic infection with hepatitis B virus (HBV) and consumption of foods contaminated with aflatoxin B1 (AFB1) are established risk factors for hepatocellular carcinoma (HCC). In lower risk areas, infection with hepatitis C virus (HCV) and alcohol consumption carry a greater attributable risk. It is unknown whether risk of HCC is affected by other factors, including genetic predisposition. To examine this issue, we are conducting cohort studies in locales with high rates of HBV infection, AFB1 exposure, and HCC.

In a preliminary analysis, we reported that risk of aflatoxin B1-related HCC is mediated by genetic variants at the aflatoxin metabolic loci, epoxide hydrolase 1 (EPHX1) and glutathione-S-transferase M1 (GSTM1). In addition, a hotspot mutation in codon 249 of the p53 tumor suppresser gene appeared to be related to the same genetic variation. In an expanded data set, we again found that the EPHX1 2 allele is significantly over represented among HCC cases. The GSTM1 locus was also associated with increased HCC risk, although the null genotype was under represented in the cases, contrary to previously findings. The GSTM1 results may indicate that the locus serves only as a marker of risk rather than a determinant. Overall, our results suggest that individual variability in AFB1 metabolism plays a significant role in AFB1-related HCC.

Lipotrope (methionine, choline, folate, and vitamin B12) insufficiency enhances the effects of AFB1 on HCC risk in experimental animals. To determine whether this phenomenon exists in humans and whether genetic variability at lipotrope-associated loci affects risk, we are studying the relationships among lipotrope status, genotypes, viral status and HCC-associated outcomes.

Both experimental and ecologic studies indicate an inverse relation between selenium status and HCC, and that total body iron stores appear to increase the risk of HCC. We are examining both hypotheses by measuring iron and selenium levels in nails and sera. Preliminary evidence suggests that selenium levels may be related to the development of HCC. We are also evaluating prospectively selenium and iron levels and correlating them with polymorphisms in relevant loci.

In vitro experiments found that 1,25-dihydroxyvitamin D3, the active metabolite of vitamin D3, inhibits the proliferation of human HCC cell lines if vitamin D receptors are expressed. It is unknown whether increased in vivo levels of vitamin D are associated with a decreased risk of HCC. To examine this question and to study whether polymorphisms in the vitamin D receptor (VDR) are related to HCC, pre-diagnostic serum levels of vitamin D metabolites and VDR genotypes will be examined in a high-risk population. Experimental studies have also consistently found an increased occurrence of primary liver cancer among animals exposed to organochlorines. It is unknown, however, whether exposure to this chemical class affects risk of liver cancer in humans. We will examine this question by measuring organochlorines in pre-diagnosis sera to determine if levels differ between individuals with and without primary liver cancer.

Keywords

• testicular cancer, liver cancer, genetic susceptibility, vitamin D, folate, organochlorines, hepatitis B virus, hormones

Selected Publications

• Tseng M, et al. "Serum ferritin concentration and recurrence of colorectal adenoma." Cancer Epidemiol Biomarkers Prev 2000; 9:625-630.
• McGlynn KA. "Environmental and host factors in testicular germ cell tumors." Cancer Invest 2001; 19:840-851.
• McGlynn K.A., et al. "International trends and patterns in primary liver cancer." Int J Cancer 2001; 94:290-296.
• Peters U, et al. "Vitamin D, calcium, and vitamin D receptor polymorphisms in colorectal adenomas." Cancer Epidemiol Biomarkers Prev 2001; 10:1267-1274.

Collaborators

DCEG Collaborators

• Louise A. Brinton, Ph.D.; Susan S. Devesa, Ph.D.; Barry I. Graubard, Ph.D.; Mark H. Greene, M.D.; Gloria Gridley, M.S.; Patricia Hartge, Sc.D.; Richard B. Hayes, D.D.S., Ph.D.; Ann W. Hsing, Ph.D.; Ulrike Peters, Ph.D.; Charles S. Rabkin, M.D.; Rashmi Sinha, Ph.D.; Tara Vogt, Ph.D..; Stephanie Weinstein, Ph.D.; Regina G. Ziegler, Ph.D.

Other NCI Collaborators

• Kenneth H. Buetow, Ph.D.

Other ScientificCollaborators

• Robert M. Bostick, M.D., University of South Carolina, Columbia, SC
• Soulemayne M. Boup, M.D., Hopital Le Dantec, Dakar, Senegal
• Paul F. Engstrom, M.D.; Alison Evans, Ph.D.; Warren D. Kruger, Ph.D.; W. Thomas London, M.D., Fox Chase Cancer Center, Philadelphia, PA
• Ralph L. Erickson, M.D., Dr.P.H., Walter Reed Army Hospital, Washington, D.C.
• E. Robert Greenberg, M.D., Dartmouth University Medical School, Hanover, NH
• Peter Holt, M.D., St. Luke's Hospital Center, New York, NY
• Fu-Min Shen, M.D., Shanghai Medical University, Shanghai, China
• David Weinberg, M.D., Thomas Jefferson Medical University, Philadelphia, PA