Cause of Familial Testicular Cancer

BACKGROUND:

Testicular germ cell tumors (TGCT) is the most common cancer in men aged 20-35, with an
increasing incidence since the mid-twentieth century.

A family history of TGCT is associated with an increased risk of the disease.

Evidence suggests that there is genetic heterogeneity in familial TGCT, thereby creating
opportunities for both new susceptibility gene discovery and searching for
genotype/phenotype/cancer correlations.

Search for genitourinary developmental anomalies and for testicular intraepithelial neoplasia
(TIN) cells which are thought to be the precursor of the vast majority of TGCT could help
clarify the etiology and identify clinical features.

This project is both etiologic and clinical in its focus, and its goal is to acquire a
comprehensive understanding of both the genetic and non-genetic factors which contribute to
the risk of familial TGCT.

OBJECTIVES:

Ascertain new families with familial testicular germ cell tumors.

Characterize the clinical features of familial TGCT.

Determine the underlying genetic mechanism for susceptibility to TGCT in families; one
specific goal is to confirm, and then to clone, the hereditary testicular cancer gene which
has been mapped to chromosome Xq27.

Evaluate various parameters related to psychosocial and behavioral issues resulting from
being a member of a family at increased risk of TGCT.

ELIGIBILITY:

A single family member with bilateral testicular cancer.

Individuals of both genders from a family with at least two cases of documented GCT in blood
relatives (at least one of which is testicular in origin) and with at least one of the GCT
cases in their family willing to participate in the study.

Men with a history of TGCT who have a monozygotic twin brother (the unaffected identical
sibling must also agree to participate).

Families will be deemed ineligible if critical informative family members lacking surviving
spouses and children are unable to provide germ line DNA

Minor children under age 12 will not be eligible for study participation.

DESIGN:

International collaboration between NCI's Clinical Genetics Branch and the International
Testicular Cancer Linkage Consortium (ITCLC), via contribution of DNA.

Non-randomized cohort study with an estimated accrual of 75 and 100 new TGCT families over a
period of 5 years and approximately 40 families willing to visit the NIH Clinical Center.

Individuals and family members will be asked to contribute baseline questionnaires as well as
questionnaires regarding lifestyle, feelings, attitudes and behavior that relate to being
part of a high-risk family, and DNA for gene mapping and cloning efforts.

Detailed, in-person, etiologically-oriented evaluation at the NIH Clinical Center includes a
comprehensive history and physical examination, laboratory testing, and ultrasound imaging of
the kidneys and gonads to identify the clinical features and seek clinically occult TGCT and
TIN. CT imaging studies of the chest, abdomen, and pelvis will be performed when indicated.

Study participants will be monitored prospectively for the development of outcomes of
interest by means of periodic mail and/or telephone contact. Cancer outcomes will be
documented through review of medical, vital, and pathology records. Tumor tissue will be
obtained whenever feasible.

- INCLUSION CRITERIA:

Study population:

Patients must be members of families with familial TGCT as defined below.

Definition of familial TGCT:

The criterion establishing familial TGCT is the presence of:

-at least two cases of documented GCT in blood relatives (at least one of which is
testicular in origin),

OR

- a single family member with bilateral testicular cancer,

- men with a history of TGCT who are one in a set of identical siblings will also be
included in the study.

Case definition:

A case will be determined to have TGCT according to the following criteria:

- Pathologic confirmation of a germ cell derived tumor arising in the testis.
Extragonadal germ cell tumors will also be included.

- Germ cell derived histologies including: seminoma, germinoma, embryonal carcinoma,
endodermal sinus (yolk sac) tumor, gonadoblastoma, choriocarcinoma, teratoma, and
mixed germ cell tumor.

- A case will be determined to have TIN on the basis of pathologic confirmation of
intratubular malignant germ cells (ITMGCs) as defined by Burke and Mostofi.

Individuals from participating families who are eligible for this study include:

i) all TGCT cases;

ii) All GCT cases (including those of ovarian or extra-gonadal sites);

iii) all first-degree relatives of each TGCT case;

iv) the spouse(s) of every case if the spouse and case had children who are participating
in the study;

v) any blood relative not included in (ii - iii) above who genetically links two cases; and

vi) any blood relative with cancer other than TGCT

vii) family members as described in i) - v) above must be age 12 or greater in order to
participate

EXCLUSION CRITERIA:

Families will be deemed ineligible for participation in this study if:

There are not at least two proven cases of GCT in the family, one of which is testicular in
origin, unless there is a family member with bilateral testicular cancer;

Deceased TGCT cases lacking both archival sources of tissue for DNA extraction AND lacking
surviving spouses and children who are willing to paricipate in the study (unavailability
of such persons prohibits inferring the genotype of the deceased individual with TGCT).

Critical informative family members are unwilling to participate (i.e., unwilling to
provide written informed consent);