Genetics of Familial Testicular Cancer
Condition: Testicular Cancer
MeSH terms: Testicular Neoplasms
Study type: Observational

Summary: 
      This study is a collaboration between the Clinical Genetics Branch of the National Cancer
      Institute and the International Testicular Cancer Linkage Consortium (ITCLC). The primary
      goal of the ITCLC is mapping and cloning susceptibility genes for familial TGCT. The
      objectives of the current study are to:

        -  Identify the genes responsible for testicular germ cell tumor (TGCT) (testicular cancer)
           in families with an inherited tendency to develop the disease

        -  Determine if the genes which predispose to developing testicular cancer also increase
           the risk of other specific types of cancer among first- and second-degree relatives of
           patients with TGCT

        -  Determine if the microscopic appearance of familial testicular cancers is different from
           that of non-familial TGCT

      Patients and family members recruited by the ITCLC in the United Kingdom, the Netherlands,
      and Norway are eligible for this study. Individuals with the following medical criteria may
      participate:

        -  Patients with testicular germ cell cancer who have at least one other blood relative
           with the disease

        -  Family members of patients (first- and second-degree relatives)

      Participants undergo the following procedures:

        -  Fill out questionnaires for providing information about a history of cancer in all blood
           relatives, including parents, siblings, children, grandparents, aunts, uncles, and
           cousins, and a history of undescended testes in male blood relatives. Participants may
           be asked permission to contact family members to request their help in the study as
           well.

        -  Provide a blood sample for genetic testing related to TGCT (except in children under 16
           years old).

        -  Review of medical records and examination of tumor specimen (patients with TGCT only).

        -  Confirmation of the diagnosis of other types of cancer in these same families (medical
           records, pathology repots)

        -  Review of the testicular cancer tissue obtained at the time of surgery from members of
           multiple case families, and comparison of these findings with a series of TGCT which
           have developed in men without a family history.
    

Detailed description: 
      Familial clustering of testicular germ cell tumors (TGCT) is well-documented, and a family
      history of TGCT is associated with an increased risk of this disease. The International
      Testicular Cancer Linkage Consortium (ITCLC) has assembled 350 multiple case TGCT families in
      support of a linkage effort that provisionally mapped a susceptibility gene to chromosome
      Xq27 in a subset of these kindreds. However, familial TGCT is genetically heterogeneous, thus
      increasing the need for meticulous case definition and classification in ongoing genetic and
      etiologic studies. The histopathologic classification of TGCT is very complicated; few
      pathologists have extensive experience reviewing this uncommon tumor. Basing epidemiologic
      studies upon local pathology reports may result in failure to recognize etiologically
      critical TGCT subsets of the kind which have been central to suspecting and defining various
      hereditary cancer syndromes, such as the multiple inherited renal cancer disorders.

      Few studies have addressed the risk of cancer among relatives of sporadic TGCT patients.
      Recent reports suggest a 20% increase in overall cancer risk among first-degree relatives of
      TGCT patients and site-specific excess cancer risks in male relatives and in the mothers of
      TGCT patients. These cancer sites constitute diseases for which there is some prior evidence
      to suggest a genetic relationship to TGCT. Identification of other cancers as part of the
      familial TGCT disease spectrum would both provide clinically relevant insight into this
      syndrome, and enhance the statistical power of gene-seeking linkage analysis.

      We propose two studies, each targeting the ITCLC set of high-risk TGCT families, none of
      which come from the US: (a) Centralized Pathology Review of Familial TGCT; and (b) The
      Occurrence of Cancer Other than Germ Cell Tumors in TGCT Families. Data will be provided by
      three of the largest ITCLC contributors; each will contact TGCT probands and their relatives
      and collect the primary data under their familial and non-familial TGCT, and perform the data
      analysis for both studies. NCI will neither seek nor receive individual identifying
      information from any participant. Currently, our UK collaborator has completed acquisition of
      a Federal Wide Assurance (FWA) and local ethical review. Since this group is contributing 70%
      of the families in these two projects, we now bring that component before the NCI Special
      Studies IRB. We shall return to the IRB for review of the other two contributors upon
      completion of their local ethical review process.
    

Observational model: Family-Based
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Families with at least two histopathologically confirmed cases of TGCT, or a combination of
        TGCT and extragonadal germ cell tumor, and with DNA from at least one affected case will be
        enrolled at the U.S., U.K., and Norwegian study sites. For the sub-studies, data will be
        obtained on all family members (siblings, parents, offspring, aunts, uncles, grandparents,
        cousins) at up to 3 degrees of genetic relatedness to the proband.
      
Biospecimen description: 
      Formalin-fixed, paraffin-imbedded H&E tissue sections from familial and sporadic testicular
      cancer tumors.
    
Keywords: Pathology; Genetics; Testicular Cancer; Familial; Cancer Epidemiology