Risk of cancer in first- and second-degree relatives of testicular germ cell tumor cases and controls†
This article is a US Government work and, as such, is in the public domain in the United States of America.
Risk factors for testicular germ cell tumors (TGCT) have not been well identified; however, data suggest that risks of cancer in family members of men with TGCT is elevated. Using family history data from 738 cases and 904 controls enrolled in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) Study from 2002 to 2005, the risk of cancer in first- and second-degree family members of these men was examined. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusting for reference age of case or control, race/ethnicity of case or control, sex of family member and lineage (maternal vs. paternal). An increased risk of all cancer among first-degree relatives of cases compared to controls was observed (RR = 1.17, 95% CI: 1.01–1.35). There were suggestions of differences in risk when stratifying all relatives by lineage. For maternal relatives, there was a statistically significant increased risk of all cancer (RR = 1.16, 95% CI: 1.04–1.30), digestive tract (RR = 1.52, 95% CI: 1.15–2.00) and male genital organ cancer (RR = 1.70, 95% CI: 1.15–2.51); there was also a suggestion of increased risks of hematopoetic cancers, cancers in the female genital organs and nonmelanoma skin cancer. For paternal relatives, there was a statistically significant association only with decreased risk of lung cancer (RR = 0.69, 95% CI: 0.51–0.94). Thus, this study suggests that there may be aggregation of cancer among families of men diagnosed with TGCT. Published 2008 Wiley-Liss, Inc.
Testicular germ cell tumors (TGCT) are the most common tumors among men in the U.S. aged 15–35 years, and the incidence of certain subtypes is still rising.1 However, with the exception of cryptorchidism, which has been shown to increase risk substantially, other risk factors for TGCT have not been well identified,2 although there is some evidence that a genetic predisposition to TGCT may exist. Several studies have shown that men with TGCT, compared to those without, are more likely to have a family member also affected with TGCT. Brothers of cases have been shown to have a 5- to 14-fold increase in risk of having TGCT,3–6 and this elevated risk is particularly evident among twins.7 Fathers of men with TGCT have also been shown to have elevated risk of having TGCT, although the increase in risk is not as high, ranging from 1.75 to 4.50.3, 4, 6, 8–10 Other studies have indicated an elevated risk of other cancers among first- and second-degree family members, including a higher risk of breast cancer8, 9, 11–14 and cancer in the female genital organs of mothers or sisters of TGCT cases.9, 11 Thus, it is reasonable to posit that there may be an increased risk of hormonally related cancers among family members of men with TGCT.
There have been several studies on aggregation of cancer among families identified by a proband with TGCT, but many of the earlier studies focused primarily on first-degree relatives, and few studies have quantitatively examined the spectrum of cancers that may aggregate with TGCT,3, 15 or, to our knowledge, have examined whether there are differences in a relative's cancer risk by lineage (maternal vs. paternal). In addition, there are no data from the U.S. on familial aggregation of cancer among relatives of probands with TGCT. Thus, we sought to characterize the risk of cancer among family members of men participating in a U.S.-based case–control study of TGCT. We examined risk of cancer in first- and second-degree relatives as well as risk by lineage (maternal vs. paternal) and by TGCT histologic type.
Material and methods
Study participants enrolled from April 2002 to January 2005 in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) Study have been previously described in detail.16 Briefly, all men who had at least 1 serum sample stored in the Department of Defense Serum Repository (Silver Spring, MD) and who were younger than 45 years of age at diagnosis were eligible for the study. Men who developed TGCT while on active duty were eligible to be enrolled as cases if they were diagnosed at a later date than the date of serum donation. TGCT diagnoses, confirmed by pathology reports or by a pathologist if the pathology report was missing (5%), were limited to classic seminomas or nonseminomas (embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, teratomas and mixed germ cell tumors). Men who developed spermatocytic seminomas were not eligible for inclusion. Eligible controls were men who did not develop TGCT and were pair-matched to cases based on age at diagnosis (<1 year), ethnicity (white, black, other) and date serum sample was donated (<30 days).
Of the possible case participants (n = 853), 22 were in the process of being contacted when the study closed, leaving 831 men who were contacted. Of those, 77 refused to participate and 754 cases (91%) agreed to participate in and completed the study. Of the possible control participants (n = 1,182), 32 were in the process of being contacted when the study closed, leaving 1,150 men who were contacted. Of those, 222 refused to participate and 928 (81%) controls agreed to participate in and completed the study. Seven hundred and twenty were matched case–control pairs. Of the cases and controls that agreed to participate, 1,247 participants also gave permission to contact their mothers; 41 mothers were found to be ineligible (primarily because of a language barrier) and 16 could not be located. Of the 1,160 mothers that were contacted, 72 refused to participate (94% participation); the remaining 1,088 women were enrolled into the study and completed a questionnaire. The study was approved by the institutional review boards of the National Cancer Institute and the Walter Reed Army Institute for Research. All participants provided written informed consent prior to enrolling in the study.
Determination of family history of cancer
Each case/control participant completed a study questionnaire through a computer-assisted telephone interview. Questionnaires elicited information on known or suspected risk factors for TGCT and a detailed family pedigree of blood relatives, including half-siblings and excluding stepparents or relations by marriage or adoption. Information collected on each relative included their age at interview if alive or age at death, whether the relative ever had a cancer diagnosis and the types and dates of cancer diagnoses. The mothers of the case/control participants were also interviewed and completed a questionnaire including the same family history information. For our determination of family history of cancer, we used any report of cancer in relatives from either the participant or their mother. If the dates of cancer diagnoses reported by the sons and mothers were discrepant, we used the date reported by the mother.
To maximize the power of our associations, cancer diagnoses were categorized into the following main groups: all malignant neoplasms, head and neck (buccal cavity, head, neck, larynx), lung, breast, digestive tract (esophagus, stomach, colorectal, pancreas, biliary tract, liver), urinary system (bladder, kidney), hematopoetic (leukemia, lymphoma, myeloma), male genital organs (penis, prostate, testis), female genital organs (uterus, vagina, vulva, cervix, ovary, fallopian tube), melanoma and nonmelanoma skin. In men, prostate and testicular cancers were also examined separately.
To assess familial aggregation, we estimated risk of cancer in relatives among men with and without a diagnosis of TGCT, by applying a general stratified Cox model, where tij denoted the age at onset of cancer or the age at censoring for member j in family i.17 The outcome tij was modeled as
where Xij denoted measured covariates for member j in family i, and Zij was an indicator variable of the proband's disease status (Zij = 1 if proband of family i is a case and 0 otherwise). Testing for familial aggregation corresponds to testing the null hypothesis H0: γ = 0. The subscript g indicated the gth stratum, and the strata were defined by cohort birth year. g was equal to 1, 2, 3, 4, 5 or 6 if the individual was born before 1920, from 1920 to 1940, from 1941 to 1960, from 1961 to 1980 and after 1980, respectively. The baseline hazard function λ0g (tij) was allowed to vary for each stratum; however, the coefficients β and γ were the same for each stratum. The parameters β and γ were estimated by maximizing a partial likelihood function, obtained by multiplying likelihood functions for each stratum under the assumption of no interaction between the stratification variable (cohort birth year) and the covariates (Xij and Zij). We estimated the variance–covariance matrix of and by the robust sandwich estimator18 using Proc Survival, in the Sudaan 9.0 program (RTI International, Research Triangle Park, NC), which accounts for the dependence of family members and allows for stratified sampling where cases and controls are treated as being sampled from separate stratum.
Family members had an event if they were reported to have been diagnosed with cancer, and age at cancer diagnosis was the time to event. Those who did not develop cancer were not considered to have had an event and were censored either at age of death or, if alive, age at the time of the case/control participant's interview. The risk of cancer was assessed for first-degree relatives, all first- and second-degree relatives combined, and for maternal and paternal relatives, separately. Analyses were also conducted separately by sex. All models were adjusted for age at diagnosis of TGCT for the case/control, race/ethnicity of the case/control and sex, when appropriate. Models assessing risk for all first- and second-degree relatives combined also adjusted for lineage (maternal vs. paternal).
We also examined differences in cancer risk of family members by TGCT histology of the proband (seminoma vs. nonseminoma) using data from the cases only. Therefore, Zij is defined as the indicator of the cases' histology status (Zij = 1 if the case of family i has a diagnosis of seminoma and 0 if the case of family i has a diagnosis of nonseminoma). These models were adjusted for race/ethnicity of case, sex (when appropriate) and lineage (when appropriate). Age at diagnosis was not adjusted for in these models, because seminomas occur primarily among older men and histology has been shown to be strongly correlated with age at diagnosis.1
Family history data were available from 738 cases and 904 controls and from the mothers of 515 cases and 556 controls. Three hundred and fourteen of the cases had been diagnosed with seminomas and 424 with nonseminomas. The mean ages of cases and controls were 28.4 and 28.3 years, respectively; within cases, the mean ages of men with seminomas and nonseminomas were 30.8 and 26.3 years, respectively.
Risk of cancer in first-degree relatives of the study participants is presented in Table I. Among all first-degree relatives of the cases, there were increased risks of all cancer [relative risk (RR) = 1.17, 95% confidence intervals (CIs), 1.01–1.35] and nonmelanoma skin cancer (RR = 1.48, 95% CI: 1.07–2.06), and a decreased risk of head and neck cancers (RR = 0.37, 95% CI: 0.15–0.94). For male first-degree relatives, although there was a statistically significant 4.51-fold increase in total testicular cancer risk, when separated, the risks of testicular cancer in brothers (RR = 4.78, 95% CI: 0.99–23.21) and fathers (RR = 3.74, 95% CI: 0.39–36.11) were suggestively elevated, but did not reach statistical significance. Among the female first-degree relatives, there was a suggestion of an increased risk of cancers of the genital organs (RR = 1.44, 95% CI: 0.96–2.15).
Table I. Risk of Cancer in First-Degree Family Members of Men with Testicular Germ-Cell Tumors Compared with Controls, Overall and Stratified by Sex
|All malignant neoplasms||361||393||1.17 (1.01–1.35)||167||192||1.07 (0.86–1.32)||194||201||1.25 (1.02–1.53)|
|Head and neck||6||20||0.37 (0.15–0.94)||3||13||0.27 (0.08–0.95)||3||7||0.54 (0.14–2.14)|
|Lung||24||36||0.84 (0.51–1.41)||11||24||0.55 (0.27–1.14)||13||12||1.44 (0.66–3.17)|
|Breast|| || || || || || ||39||51||0.99 (0.65–1.50)|
|Digestive tract||31||45||0.86 (0.53–1.37)||17||26||0.73 (0.39–1.34)||14||19||1.02 (0.51–2.07)|
|Urinary system||8||12||0.82 (0.30–2.20)||6||10||0.71 (0.25–2.04)||2||2||1.24 (0.17–9.33)|
|Hematopoetic||19||21||1.15 (0.60–2.22)||11||18||0.77 (0.36–1.65)||8||3||3.46 (0.90–13.29)|
|Male genital organs|| || || ||47||41||1.41 (0.91–2.16)|| || || |
| Testis|| || || ||14||4||4.51 (1.21–16.81)|| || || |
| Prostate|| || || ||32||36||1.06 (0.65–1.71)|| || || |
|Female genital organs|| || || || || || ||54||48||1.44 (0.96–2.15)|
|Melanoma skin||16||12||1.71 (0.79–3.70)||7||5||1.85 (0.60–5.74)||9||7||1.69 (0.63–4.56)|
|Nonmelanoma skin||81||69||1.48 (1.07–2.06)||50||38||1.66 (1.09–2.54)||31||31||1.28 (0.78–2.09)|
Risks of cancer in first- and second-degree relatives of the study participants are presented in Table II. Again, there was an increased risk of cancer in all relatives, although the association was stronger in females (RR = 1.19, 95% CI: 1.07–1.32). Significantly increased risks of digestive tract cancer, hematopoetic cancer, melanoma and nonmelanoma skin cancer were also observed. In contrast, there was a decreased risk of lung cancer, particularly among male relatives (RR = 0.78, 95% CI: 0.62–0.99). Again, we observed a statistically significant increased risk of testicular cancer (RR = 3.03, 95% CI: 1.47–6.21) and a suggestion of an increased risk of female genital organ cancer (RR = 1.27, 95% CI: 0.98–1.65). There was also a significantly increased risk of prostate cancer (RR = 1.39, 95% CI: 1.07–1.81).
Table II. Risk of Cancer in Family Members of Men with Testicular Germ-Cell Tumors Compared with Controls, Overall and Stratified by Sex
|All malignant neoplasms||1,574||1,735||1.14 (1.05–1.24)||831||879||1.16 (1.04–1.30)||657||776||1.08 (0.95–1.21)|
| Male||753||849||1.08 (0.97–1.21)||329||349||1.11 (0.94–1.32)||389||473||1.02 (0.88–1.19)|
| Female||821||886||1.19 (1.07–1.32)||502||530||1.20 (1.05–1.37)||268||303||1.15 (0.97–1.37)|
|Head and neck||46||68||0.84 (0.56–1.26)||26||34||0.93 (0.53–1.64)||18||28||0.79 (0.43–1.44)|
| Male||30||48||0.76 (0.47–1.21)||16||19||0.99 (0.49–2.01)||13||25||0.63 (0.32–1.24)|
| Female||16||20||1.02 (0.50–2.09)||10||15||0.83 (0.35–2.00)||5||3||2.13 (0.51–8.95)|
|Lung||186||282||0.81 (0.66–1.00)||106||136||0.93 (0.71–1.23)||78||143||0.69 (0.51–0.94)|
| Male||122||189||0.78 (0.62–0.99)||63||85||0.87 (0.62–1.22)||58||102||0.71 (0.51–0.98)|
| Female||64||93||0.88 (0.63–1.25)||43||51||1.07 (0.69–1.65)||20||41||0.65 (0.37–1.15)|
|Breast||209||244||1.09 (0.89–1.33)||127||151||1.05 (0.82–1.36)||77||85||1.16 (0.84–1.61)|
|Digestive tract||223||213||1.29 (1.06–1.58)||127||101||1.52 (1.15–2.00)||94||108||1.09 (0.81–1.46)|
| Male||111||119||1.13 (0.87–1.47)||54||46||1.36 (0.92–2.03)||55||70||0.96 (0.67–1.40)|
| Female||112||94||1.50 (1.13–2.00)||73||55||1.65 (1.15–2.37)||39||38||1.32 (0.84–2.08)|
|Urinary system||42||48||1.09 (0.71–1.67)||26||27||1.16 (0.66–2.04)||15||19||1.04 (0.53–2.05)|
| Male||31||29||1.32 (0.80–2.20)||18||13||1.66 (0.80–3.42)||12||14||1.13 (0.52–2.43)|
| Female||11||19||0.72 (0.34–1.53)||8||14||0.68 (0.28–1.64)||3||5||0.79 (0.18–3.38)|
|Hematopoetic||86||86||1.25 (0.90–1.72)||47||39||1.50 (0.96–2.34)||31||43||0.89 (0.55–1.44)|
| Male||44||53||1.02 (0.67–1.56)||23||18||1.52 (0.79–2.90)||16||33||0.60 (0.33–1.09)|
| Female||42||33||1.61 (1.02–2.56)||24||21||1.47 (0.81–2.66)||15||10||1.83 (0.79–4.22)|
|Male genital organs||175||144||1.52 (1.19–1.94)||70||50||1.70 (1.15–2.51)||94||91||1.30 (0.94–1.80)|
| Testis||28||12||3.03 (1.47–6.21)||12||4||3.85 (1.22–12.12)||5||5||1.34 (0.38–4.78)|
| Prostate||146||130||1.39 (1.07–1.81)||58||46||1.52 (1.00–2.32)||88||84||1.32 (0.94–1.84)|
|Female genital organs||132||132||1.27 (0.98–1.65)||85||82||1.29 (0.95–1.74)||22||26||1.07 (0.59–1.94)|
|Melanoma skin||29||40||0.94 (0.57–1.55)||16||25||0.80 (0.42–1.52)||8||11||0.95 (0.37–2.45)|
| Male||13||22||0.75 (0.37–1.52)||4||12||0.41 (0.13–1.25)||6||8||0.97 (0.31–2.98)|
| Female||16||18||1.34 (1.01–1.77)||12||13||1.19 (0.53–2.63)||2||3||0.91 (0.16–5.27)|
|Nonmelanoma skin||184||169||1.40 (1.10–1.77)||92||85||1.35 (0.96–1.91)||79||73||1.41 (0.99–1.99)|
| Male||109||102||1.17 (0.59–2.31)||38||35||1.31 (0.79–2.18)||62||62||1.29 (0.90–1.84)|
| Female||75||67||1.49 (1.04–2.11)||54||50||1.39 (0.92–2.10)||17||11||2.20 (0.98–4.93)|
When stratified by lineage (Table II), there were increased risks of all cancer (RR = 1.16, 95% CI: 1.04–1.30), digestive tract cancer (RR = 1.52, 95% CI: 1.15–2.00), testicular cancer (RR = 3.85, 95% CI 1.22–12.12) and prostate cancer (RR = 1.52, 95% CI 1.00–2.32) among maternal relatives. There were also suggestions of increased risks of hematopoetic cancers, female genital organ cancers and nonmelanoma skin cancer. Among the paternal relatives, there was only a suggestion of an increased risk of all cancer (RR = 1.08, 95% CI: 0.95–1.21), prostate cancer (RR = 1.32, 95% CI: 0.94–1.84) and nonmelanoma skin cancer (RR = 1.41, 95% CI: 0.99–1.99). Risk of testicular cancer was not statistically significantly elevated among the paternal relatives (RR = 1.34, 95% CI: 0.38–4.78); however, there was a reduction in lung cancer risk in male paternal relatives (RR = 0.71, 95% CI: 0.51–0.98) that was not observed among the male maternal relatives (OR = 0.87, 95% CI: 0.62–1.22).
Cancer risks among relatives stratified by tumor histology of the proband's TGCT were also examined (Table III). Because of small numbers, however, there was insufficient power to examine risks of head and neck cancers, urinary system cancers or melanoma. When comparing seminoma to nonseminoma, first-degree relatives of men with seminoma had a 20% reduction in risk of all cancer (95% CI: 0.65–1.00). There was also a reduction in risk of lung cancer (RR = 0.44, 95% CI: 0.19–0.98) and nonmelanoma skin cancer (RR = 0.52, 95% CI: 0.33–0.82). For maternal relatives, there was a statistically significant increased risk of all cancer and lung cancer in male relatives and decreased risk of hematopoetic cancer in female relatives of men with seminoma. For paternal relatives, there were no differences in cancer risk for relatives of men with seminoma vs. nonseminoma, except for a statistically significant inverse association of nonmelanoma skin cancer.
Table III. Risk of Cancer in Family Members of Men with Seminomatous Testicular Germ-Cell Tumors Compared with Nonseminomas, Overall and Stratified by Sex
|All malignant neoplasms||187||174||0.80 (0.65–1.00)||685||889||1.01 (0.89–1.14)||336||495||1.14 (0.96–1.35)||303||354||0.90 (0.76–1.08)|
| Male||87||80||0.81 (0.59–1.11)||327||426||1.06 (0.90–1.26)||124||205||1.31 (1.00–1.72)||188||201||0.89 (0.71–1.10)|
| Female||100||94||0.79 (0.59–1.06)||358||463||0.97 (0.83–1.13)||212||290||1.04 (0.85–1.27)||115||153||0.46 (0.18–1.16)|
|Lung||16||8||0.44 (0.19–0.98)||79||107||1.10 (0.80–1.51)||39||67||1.42 (0.92–2.18)||39||39||0.81 (0.50–1.31)|
| Male||7||4||0.54 (0.18–1.63)||47||75||1.35 (0.93–1.95)||20||43||1.79 (1.05–3.05)||27||31||0.99 (0.59–1.66)|
| Female||9||4||0.38 (0.12–1.22)||32||32||0.76 (0.44–1.32)||19||24||1.02 (0.51–2.04)||12||8||1.09 (0.68–1.76)|
|Breast||17||22||1.19 (0.63–2.27)||79||130||1.119 (0.89–1.61)||45||82||1.36 (0.93–1.98)||30||47||0.59 (0.30–1.15)|
|Digestive tract||15||16||1.02 (0.49–2.09)||93||130||1.11 (0.83–1.49)||50||77||1.28 (0.87–1.89)||42||52||0.94 (0.60–1.47)|
| Male||8||9||1.08 (0.43–2.70)||41||70||1.41 (0.97–2.04)||19||35||1.60 (0.92–2.77)||21||34||1.31 (0.76–2.28)|
| Female||7||7||0.95 (0.33–2.69)||52||60||0.91 (0.61–1.37)||31||42||1.12 (0.67–1.87)||21||18|| |
|Hematopoetic||11||8||0.57 (0.21–1.55)||42||44||0.79 (0.51–1.24)||22||25||0.80 (0.45–1.41)||15||16||0.84 (0.41–1.74)|
| Male||5||6||0.95 (0.28–3.22)||17||27||1.21 (0.65–2.27)||7||16||1.56 (0.64–3.82)||8||8||0.82 (0.30–2.26)|
| Female||6||2||0.27 (0.05–1.35)||25||17||0.50 (0.27–0.94)||15||9||0.44 (0.19–0.98)||7||8||0.83 (0.28–2.42)|
|Male genital organs||35||30||1.23 (0.68–2.22)||75||100||1.09 (0.75–1.57)||26||44||1.25 (0.72–2.15)||45||49||0.92 (0.56–1.51)|
| Testis||6||8||0.96 (0.33–2.82)||12||16||0.97 (0.45–2.09)||6||6||0.60 (0.20–1.77)||2||3||0.92 (0.16–5.12)|
| Prostate||29||21||1.27 (0.63–2.57)||63||83||1.10 (0.73–1.64)||20||38||1.46 (0.77–2.75)||43||45||0.90 (0.54–1.51)|
|Female genital organs||26||28||0.85 (0.49–1.49)||52||80||1.16 (0.81–1.67)||33||52||1.16 (0.75–1.79)||6||16||1.93 (0.67–5.56)|
|Nonmelanoma skin||50||31||0.52 (0.33–0.82)||102||82||0.60 (0.43–0.85)||47||45||0.71 (0.43–1.17)||48||31||0.49 (0.30–0.82)|
| Male||29||21||0.60 (0.35–1.05)||58||51||0.69 (0.47–1.02)||17||21||0.96 (0.44–2.08)||36||26||0.58 (0.34–0.96)|
| Female||21||10||0.40 (0.19–0.81)||44||31||0.50 (0.30–0.83)||30||24||0.58 (0.32–1.03)||12||5||0.28 (0.09–0.87)|
Our findings of an increased risk of testicular cancer in male first-degree relatives, especially in brothers, is consistent with the majority of studies examining familial aggregation of cancers.3, 4, 6, 8–10, 15, 19 First-degree relatives were observed to have increased risks of female genital organ, hematopoetic and nonmelanoma skin cancer and a decreased risk of head and neck cancer. Associations for female genital cancer have also been inconsistent, with 3 studies reporting increased risks5, 8, 11 and 4 studies reporting no association.3, 9, 15, 19 Risk associated with hematopoetic cancers have been inconsistent, with 1 study reporting an increased risk in mothers,9 one reporting decreased risk3 and others finding no association.6, 15, 19 No studies have previously observed an association with nonmelanoma skin cancer,3, 9 although 2 studies have reported an increased risk of melanoma.3, 9 The suggestion of an increased risk of melanoma observed in this study (OR = 1.71, 95% CI: 0.79–3.70), however, did not attain statistical significance. Two prior studies have reported the rate of head and neck cancers among relatives of TGCT cases compared to controls. Although Gundy et al.19 did not calculate a RR, there were fewer first-degree family members of cases with head/neck cancer (n = 10) than first-degree family members of controls (n = 17); however, these differences are not likely to be statistically significant. Another study reporting on mouth and pharynx cancer calculated an observed/expected ratio of 0.5 (95% CI: 0.1–1.8).15 The findings of these studies and ours may be due to chance because of small numbers of cases.
Other cancers that have been reported to aggregate with testicular tumors in first-degree family members include colorectal cancers,3, 9 lung or other respiratory tract cancers,5, 9, 15 kidney cancer3 and breast cancer.8, 9, 11 These previous findings have been inconsistent, as other studies have reported a reduction in cancer risk, among first-degree relatives in the urinary tract,15 gastrointestinal tract6 and respiratory tract.6, 11 Our study was unique in its ability to examine cancer risk among first- and second-degree relatives. With the expanded family size, we also observed familial aggregation of cancers in the digestive tract and prostate and a reduced risk of lung cancer. The lack of an association seen with prostate cancer in most other studies may be due, in part, to differential screening practices between the northern European countries and the U.S. studies of family history also found positive associations between TGCT risk and history of maternal lung cancer,20 maternal breast cancer13 and prostate and breast cancer in first- and second-degree relatives.14
The observed differences in associations between sex and lineage are interesting and may be clues to the etiology of TGCT. Aggregation of cancer in families of men with TGCT could be due to inheritance of traits, such as genetic variation or inherited epigenetic modification, and/or common environmental risk factors. It is unknown, though, what proportion of TGCT risk may be explained by each of these components. The observation of stronger increases in all cancer risk among brothers and sisters of men with TGCT than among parents, suggests that a common in utero exposure may be associated with an increased cancer risk.21, 22 Alterations in hormonal concentrations during pregnancy or within the affected individuals themselves, either because of genetics or common environmental exposures among family members, may also explain the increased risk of other hormonally related cancers that we have observed in family members of TGCT cases. Linkage analyses of TGCT have not identified any single major locus that can account for the majority of the familial aggregation of TGCT, but rather suggest that multiple susceptibility loci with weak effects are involved.23–25 Although there has been a suggestion of a role of X linkage in families with 2 or more cases of TGCT,24 these results have not yet been verified by other studies.25 Two of our notable findings were the suggestions of increased risks of melanoma and nonmelanoma skin cancer. These cancers, like TGCT,26 have substantial variation due to geographic differences,26, 27 with men in northern Europe and in the U.S. having the highest rates. These observations again suggest that both genetic and environmental factors may be responsible.
There are several considerations that must be taken into account when interpreting the results of our study. This case–control study of TGCT in the U.S. had a large number of person-years, and we were able to assess risk of cancer among first- and second-degree relatives. We were also able to examine a spectrum of cancers, although power was limited in some of the rarer cancers. Although our participation rates were generally high, there is the possibility that selection bias may affect our results as participation proportions between cases and controls were different. This is the first study to examine familial aggregation in maternal and paternal relatives separately. There is a chance, however, that retrospective determination of family history of cancer could lead to misclassified outcomes, as cancer diagnoses were not able to be verified and agreement between the proband's and their mother's reports of cancer among relatives was 63%. In addition, because family history was collected from the proband's mother, but not his father, there is the possibility that reporting may be more accurate for the maternal lineage. This could have led to the differential risk estimates observed when cancer outcomes were stratified by lineage. However, studies have shown that the accuracy of a proband reporting on cancer among first-degree relatives is high, ranging from 83 to 95%, although accuracy of reporting on a second-degree relative was significantly lower.28, 29
Our study results suggest that there may be familial aggregation of cancer in men with TGCT, and there are suggestions there may be differences by lineage. Although no single major locus has been found to explain the high risk of TGCT in brothers of men with TGCT, there is a strong suggestion that either many loci contribute to the familial aggregation of TGCT and other cancers, or that shared environmental exposures, including the determination of hormonal concentrations, are responsible.
The authors thank Emily Steplowski of Information Management Services, Inc. (Rockville, Maryland) for her contributions to data management. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.