Genome-Wide Association Study of Sporadic and Familial Testicular Germ Cell Tumors

Case-Control Study:
Testicular germ cell cancer has been increasing among men during most of the 20th century. Despite this increase, the etiology of testicular cancer is poorly understood. To better understand the molecular epidemiology of testicular cancer, the National Cancer Institute and the Department of Defense are conducting a case-control study of testicular cancer among military servicemen. The project includes obtaining biosamples and questionnaire data from all participants. Pre-diagnostic serum samples are available from the approximately 1,000 cases and 1,000 controls enrolled in the study.

Multiple-Case Family Study:
In a parallel project, we are also studying families in which 2 or more testicular cancers have occurred. Among those men diagnosed with testicular cancer, about 1-3 percent report a family history of the disease (FTGCT). Brothers of affected individuals are 8 to 10 times more likely to develop testicular cancer, and men whose fathers had testicular cancer are four times more likely to develop testicular cancer, when compared with the relatives of men who have never had testicular cancer. Large-scale genetic linkage studies have failed to identify one or more rare, highly-penetrant testicular susceptibility genes. Rather, it appears that these familial clusters are due to the combined effects of multiple more common genes with low penetrance (so-called "polygenic inheritance"). Our cohort of FTGCT families was assembled to characterize this syndrome's clinical phenotype, and to discover the full range of cancer susceptibility loci that influence TGCT pathogenesis.

• Study Weblinks:
  • Familial Testicular Cancer Study
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Family
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1509
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• Gene
• PMC

Case-Control Study:
The study was designed as a pair-matched, case-control study, although additional controls were initially identified because of the transient nature of the military population. By use of the computerized Defense Medical Surveillance System database, all available controls were identified for each potential case participant. From the list of possible controls, four individuals who matched each case on age (within 1 year), race (White, Black, other), and date of available serum sample (within 30 days) were chosen at random as the control set. The first man on the list was designated as the primary control. Every attempt was made to enroll this man for 30 days (average number of attempted contacts = 90). The effort included tracing attempts, multiple letters, and telephone calls. If the man could not be traced, was deployed to a combat zone, was deceased, refused to participate, or could not be contacted within a 30-day period, attempts were begun to enroll the next possible control in the set.

The database linkage identified 961 cases who appeared to meet the study criteria. Further review found that 76 men could not be traced, 27 had died, three were known to be deployed to a combat zone, and two were found ineligible, leaving 853 possible participants. Of these men, 22 were in the process of being contacted when the study closed. Thus, of the 831 men contacted, 754 agreed to participate, resulting in a participation rate of 91 percent. In the instances where the potential case was deceased, the study attempted to obtain proxy information from the man's mother. Thirteen proxy questionnaires were completed by the mothers of the 27 deceased men. Among the controls, 2,579 were evaluated for inclusion. Of these men, 385 men could not be traced, 18 had died, 64 were known to be deployed to a combat zone, and two were found to be ineligible. In addition, 928 could not be contacted within 30 days. Of the remaining 1,182 men, 32 were in the process of being contacted when the study closed. Thus, of the 1,150 men contacted, 928 agreed to participate, resulting in a participation rate of 81 percent. Among the 754 cases and 928 controls, there were 720 matched case-control pairs.

Multiple-Case Family Study:
Familial testicular cancer kindred were identified through mailings to the members of health care provider societies who were likely to encounter TGCT patients in the course of their practice, a study-specific website, and various TGCT patient support/family advocacy groups. Criteria for enrollment into the study include at least one of the following: 1) ≥two men in the family had testicular cancer, 2) one family member has bilateral testicular cancer (that is, independent cancers involving both testicles), or 3) one family member with testicular cancer is a member of a set of genetically identical brothers, such as twins or triplets. We have recruited 733 members from 151 multiple-case families, and collected 649 DNA samples for our genetic analyses. Willing families were brought to the NIH Clinical Center for a 2-day, in-person evaluation by our multidisciplinary team. We collected demographic, family history, cancer risk factor and behavioral/psychosocial data, performed TGCT-related imaging studies and collected a variety of biological specimens. Family members who were unable or unwilling to travel to NIH completed study questionnaires and contributed biological specimens in their home communities. We attempted to objectively verify every cancer reported among bloodline family members.

All individuals were genotyped on the Illumina 660K microarray SNP chip. Standard protocols for genotyping quality control (QC) were implemented. Individuals with missing rate > 0.06 and/or autosomal heterozygosity 0.35 (N=61) and SNPs with missing rate >0.1 and/or Hardy-Weinberg equilibrium p-value <1x10^-7 were excluded. No individuals with cryptic relatedness (IBD >45%) or unexpected duplicate were detected. Genotype concordance rate from 41 expected duplicates was >99.9%.

• Primary Phenotype: Germinoma

• RAD51C
• UCK2
• MAD1L1
• PPM1E
• HPGDS
• RFWD3
• TEX14

• Principal Investigator Case-Control Study
  • Katherine McGlynn. National Institutes of Health, Bethesda, MD, USA.
• Principal Investigator Multiple-Case Families
  • Mark H. Greene. National Institutes of Health, Bethesda, MD, USA.
• Funding Source
  • NIH Intramural Program. National Institutes of Health, Bethesda, MD, USA.