The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. Despite three decades of research in human populations, the etiology of TGCC remains obscure and our knowledge of risk factors is limited largely to demographic characteristics and a history of undescended testes. Clinical, non-human experimental, and epidemiologic studies of TGCC have provided evidence that exposure to abnormal levels of steroid hormones, either in utero, perinatally, and/or early in life, may be a key etiologic factor for TGCC.   Recent progress in identifying polymorphisms in genes contributing to endogenous steroid hormone metabolism presents an opportunity to expand beyond the scope of prior epidemiologic studies by addressing the hypothesized hormonal etiology of TGCC at the molecular genetic level. Thus, in June 2000 we initiated a population-based case-control study funded by the National Cancer Institute to test the hypothesis that inherited variation in genes involved in stimulating testicular steroidogenesis, synthesizing and metabolizing testosterone, and androgen signaling, is related to the risk of developing TGCC. My primary collaborators are Drs. Chu Chen, Noel Weiss , and Jackie Starr.

This case-control study has provided a platform for initiating two ancillary studies that also relate to the role of molecular and genetic factors in TGCC. In October 2001 we received funding under a joint National Institute of Occupational Safety and Health/National Cancer Institute initiative  to use biological samples collected in the case-control study to test the hypothesis that persistent endocrine disrupting chemicals, such as p,p'-DDE and polychlorinated biphenyls, influence TGCC risk. A relatively unique aspect of this project is that we will be examining explicit genetic factors, such as polymorphisms in the androgen receptor gene, for their role in modifying any risk associated with endocrine disrupting chemicals.

A second ancillary study focuses on the role of the in utero environment in determining TGCC risk. We are recruiting parents of TGCC cases enrolled in the case-control study, and collecting DNA and interview data from  these mothers and fathers. Using recently developed statistical methods, we will then assess whether maternal genetic factors (representing in utero exposure to steroid hormones and other chemicals thought to influence TGCC) influence the risk of TGCC in sons. This project has also led to methodological work on the properties of the case-parent triad method for assessing maternal and offspring genetic associations.

In a third ancillary study initiated in January 2005, we received funding from the Lance Armstrong Foundation to investigate whether variation in three germ cell survival factors--POU5F1, SOX2, and FOXD3--are risk factors  for TGCC. The first phase of the project involves re-sequencing each of these genes using DNA from 23 European-descent individuals and 24 African-American individuals to discover single nucleotide polymorphisms (SNPs) and other types of genetic variation. This phase involves assessing linkage disequilibrium patterns among the SNPs to identify a minimum set of maximally informative polymorphisms (tagSNPs) for use in association tests. The second phase involves assaying the chosen tagSNPs in ~285 cases and ~740 controls to determine whether the variation in POU5F1, SOX2, or FOXD3 is a risk factor for TGCC.

Related Publications

Starr JR, Hsu L,Schwartz SM.Assessing maternal genetic associations using the log-linear approach to case-parent triad data: Exploration of type I error, power, and bias in comparison to a case-control approach. Epidemiology. In Press

Starr JR, Hsu L, Schwartz SM. Performance of the log-linear approach to case-parent triad data for assessing maternal genetic associations with offspring disease: Type I error, power, and bias. Am J Epidemiol 2005 161: 196-204.

Biggs ML, Schwartz SM. Differences in testis cancer survival by race and ethnicity: a population-based study, 1973-99. Cancer Causes Control 2004; Jun;15(5): 437-444.