Familial Testicular Cancer Research Articles

Testicular germ cell tumour presenting as thyrotoxicosis

1994; 331: 1731–8 3 http://www.mims.com.au (last cited 11/6/2004) 4 Chowdhury TA, Tanchel BM, Jaganathan RS, Dodson PM. A toxic testicle. Lancet 2000; 355: 2046 5 Cole LA. Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. Clinical Chemistry 1997; 43: 2233–43 6 Glinoer D. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocrine Reviews 1997; 18: 404–33 7 Horwich A, Huddart R, Deamsley D. Markers and management of germ-cell tumours of the testes. Lancet 1998; 352: 1535–8 8 Forman D, Oliver RTD, Brett AR, et al. Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA Class 1 sib-pair analysis. Br J Cancer 1992; 65: 255–62 9 Klein I and Ojamaa K. Thyroid hormone and the cardiovascular system. N Eng J Med 2001; 344: 501–9 10 Osman F, Gammage MD, Sheppard MC and Franklyn JA. Cardiac dysrhythmias and thyroid dysfunction: the hidden menace. JCEM 2002; 87: 963–7 11 Tran HA, Kay SE, Kende M, Doery JCG, et al. Thyrotoxic, hypokalaemic periodic paralysis in Australasian men. Intern Med J 2003; 33: 91–4

Testicular, Other Genital, and Breast Cancers in First-Degree Relatives of Testicular Cancer Patients and Controls

Abstract Previous studies showed an increased prevalence of testicular cancer among fathers and brothers of testicular cancer patients. We examined whether testicular, other genital, and breast cancers aggregate in parents and siblings of testicular cancer patients in a population-based case-control study, including males, ages 15 to 69 years at diagnosis, with primary malignant tumors of the testes or extragonadal germ cell tumors. Controls were ascertained through the mandatory registries of residents and frequency matched to the cases by age and region of residence. In a face-to-face interview, 269 cases and 797 controls provided health-related information on parents and siblings. We calculated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) based on the generalized estimating equations technique, adjusting for the matching variables and relatives' age. Three (1.1%) fathers and eight (3.2%) brothers of cases were affected with testicular cancer compared with four (0.5%) fathers and two (0.2%) brothers of controls. The OR (95% CI) of familial testicular cancer was 6.6 (2.35-18.77). Only nonseminoma patients had fathers with testicular cancer, whereas the affected brothers were all related to seminoma patients. Overall, we found an increased risk for genital other than testicular cancers (OR 2.5, 95% CI 1.43-4.43). For breast cancer, we detected an increased risk in sisters (OR 9.5, 95% CI 2.01-45.16, adjusted for age of study participant and age of sister) but not in mothers. Our findings support the hypothesis that testicular and other genital cancers have a common familial component that may be due to genetic and shared exogenous factors such as estrogen exposure during fetal development.

Familial testicular cancer and second primary cancers in testicular cancer patients by histological type

The Swedish Family-Cancer Database was used to assess familial cancer risks in first-degree relatives and the risks of second primary cancers in testicular cancer patients by the histological type of their testicular cancers. Standardised incidence ratios (SIRs) were employed to estimate cancer risks. Among 4650 patients, 1.3% were familial testicular cancer. Seminomas showed a 10 years later median age of onset than teratomas (30 versus 40 years). The familial risks of testicular cancer were 3.8 for fathers, 8.3 for brothers and 3.9 for sons; they were similar for the two histologies. The fraternal risks were elevated 2- to 2.8-fold for pure histologies compared with the mixed histologies. Significantly increased risks for subsequent cancers were observed in the stomach, pancreas, testis, kidney, bladder, thyroid and connective and lymphatic tissues in the patients. Our data support the contention that genetic predisposition is one of the major contributors to familial and multiple testicular cancers.

Familial testicular cancer in a single-centre population

Familial occurrence of testicular cancer suggests a genetic predisposition to the disease. A genetic susceptibility may also be reflected by the occurrence of bilateral testicular neoplasms and the high rates of urogenital developmental anomalies in families prone to testicular cancer. In this study, the proportion of familial testicular cancer cases was analysed retrospectively in a single-centre population of 693 testicular cancer patients treated between 1977 and 1997 and the relative risk (RR) for first-degree relatives of patients was estimated. In addition, the existence of bilateral testicular neoplasms and urogenital developmental anomalies in familial testicular cancer patients was evaluated. 24 of the 693 patients (3.5%) had a first-degree relative with testicular cancer. These 24 cases belonged to 17 families; in 7 of these 17 families both affected first-degree family members were part of the study population of 693 patients. Consequently, the 693 studied patients belonged to a total of 686 families. Thus, the actual proportion of familial testicular cancer was 2.5% (17 of 686 families). The familial cases consisted of 11 brother pairs, including 2 pairs of identical twins and 1 pair which also had two affected cousins, and 6 father–son pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first-degree relatives showed a 9- to 13-fold increased RR to brothers ( P<0.001) and a 2-fold increased RR to fathers ( P=non-significant (n.s)) of testicular cancer patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on familial occurrence of testicular cancer may lend support to a role of genetic factors in the aetiology of testicular cancer.

The prevalence of familial testicular cancer

Undescended testes and antecedent testicular tumor are recognized risk factors for testicular germ cell cancer. It has been suggested that a family history of testicular cancer constitutes another major risk indicator. This postulation is mainly based on clinical observations and on very few systematic investigations. In the current study, the authors analyzed the proportion of familial testicular cancer in their study population and estimated the relative risk created by a family history of the disease. The proportion of familial testicular cancer was analyzed in a prospective multicentric study involving 1692 patients. The median ages of patients with and without a family history of the disease were compared. In a different patient population consisting of 518 patients and 531 age-matched controls, the frequency of family history was investigated and the relative risk calculated. In addition, a literature survey was performed to look for previous systematic reports on familial testicular cancer. In the prospective study, 18 patients (1.1%; 95% confidence interval, 0.63-1.68%) had a first-degree relative afflicted with testicular cancer. Age at presentation was not significantly different between patients with a family history and those without. In the retrospective series, the proportion of those with a family history was 1.7% (95% confidence interval [CI], 0.80-3.27%). There was a 3.1-fold increased relative risk (95% CI, 0.77-17.95) for first-degree relatives of patients with testicular cancer. Ten previous reports on familial testicular cancer were identified in the literature. Combining the results of those previous reports and the current study led to a weighted mean prevalence of familial testicular cancer of 1.35% (95% CI, 1.12-1.58%). The current study underscores that susceptibility to testicular germ cell cancer is influenced by genetic factors. A family history of testicular cancer is encountered in about 1.35% of patients. The relative risk for first-degree relatives of patients with the disease is increased by a factor of 3-10.

Familial testicular cancer in Norway and Southern Sweden: K. Heimdal, H. Olsson, S. Tretli, et al. Br J Cancer 73:964–969, (April), 1996

Familial testicular cancer in Norway and Southern Sweden: K. Heimdal, H. Olsson, S. Tretli, et al. Br J Cancer 73:964–969, (April), 1996

Cancer risk in fathers and brothers of testicular cancer patients in Denmark. A population‐based study

There are several reports of familial testicular cancer in the literature but few systematic attempts have been made to estimate the risk of testicular cancer in first-degree relatives of patients with this neoplasm, and the risk remains to be fully assessed in population-based studies. By means of data from the Danish Cancer Registry, we identified all testicular cancer patients (index cases) born and diagnosed during 1950–1993 in Denmark. Their fathers were identified from national registries, as were the brothers of a subcohort of these patients. Familial cancer occurrence was determined through linkage with the cancer registry and compared with the cancer incidence in the general male population in Denmark. The ratio of observed to expected cancers generated the measure used for the relative risk. Fathers of 2,113 index cases with testicular cancer experienced an almost 2-fold risk of developing testicular cancer themselves (RR = 1.96; 95% CI: 1.01–3.43). Overall, the fathers had a decreased relative cancer risk (RR = 0.84; 95% CI: 0.74–0.95) with a significantly decreased risk of cancers of the lung and digestive organs. Brothers of a subcohort of 702 index cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI: 3.37ndash;31.5). In conclusion, we documented a significantly increased familial risk of testicular cancer which was relatively more pronounced between brothers than between fathers and sons. These findings support the possible involvement of a genetic component in the aetiology of testicular cancer, but also leave room for a hypothesized influence of in-utero exposures, such as specific maternal hormone levels, that might be shared by brothers. © 1996 Wiley-Liss, Inc.

Familial testicular cancer in Norway and southern Sweden

Information about occurrence of testicular cancer (TC) in relatives of TC patients has been collected using questionnaires from 797 out of 922 consecutive Norwegian and 178 out of 237 Swedish patients with TC seen at the Norwegian Radium Hospital and the University Hospital Lund in Sweden during 1981-91. Fifty-one Norwegian and five Swedish patients had a relative with confirmed TC. Thus, 51/922 (5.5%) of the Norwegian and 5/237 (2.1%) of the Swedish patients treated during the time interval investigated were considered to have familial TC. Thirty-two of the patients had an affected first-degree relative. Expected numbers of cancers in the relatives were computed from data in the Norwegian and Swedish Cancer Registries. Standardised incidence ratios (SIRs) were taken as observed numbers of TC/expected numbers of TC in the relatives. The SIR for brothers was 10.2 (95% confidence interval 6.22-15.77). SIR for fathers was 4.3 (1.6-9.3) and for sons 5.7 (0.7-23.2). The point estimate for the risk to brothers in the Norwegian part of the sample to develop TC by the age of 60 was 4.1% (95% CI 1.7-6.6%). This study indicates that genetic factors may be of greater importance in TC than previously assumed. Patients with familial testicular cancer had bilateral tumours more often than sporadic cases (9.8% bilaterality in familial vs 2.8% in sporadic cases, P=0.02). For patients with seminoma age of onset was lower in familial than in sporadic cases (32.9 vs 37.6 years, P=0.06). In father-son pairs, there was a statistically significant earlier age of diagnosis in the generation of sons (28.8 years vs 44.9 years, P=0.04). The prevalence of undescended testis (UDT) did not seem to be higher in familial than in sporadic TC (8.2% in familial TC and 13.3% in sporadic cases). This may indicate that different factors are of importance for the development of familial TC and UDT.

Familial testicular cancer in a population-based cancer registry.

The population-based Connecticut Tumor Registry was used to identify 18 testicular cancer cases (diagnosed 1973-1991) with a family history of testicular cancer (including 4 father-son pairs and 8 sibling pairs) and to describe the age at diagnosis, histology and other characteristics of these familial cases. Collaboration among cancer registries is needed to identify cases for genetic studies.

High resolution chromosome banding in search of germ line mutations applied on testicular cancer patients

Patients with bilateral and/or familial testicular cancer are assumed to demonstrate germ line mutations if such mutations are instrumental in testicular cancer patients. Constitutional rearrangements have to our knowledge not been reported, while an increased level of constitutional chromosome instability has been claimed. Lymphocytes from 12 Norwegian patients with bilateral or familial testicular cancer have been studied by high resolution Giemsa banding. A possible germ line mutation would be expected to be seen in every cell. It is therefore sufficient to examine one pair of the individual chromosomes obtained, if necessary, from several cells. Based on our previous findings of loss of heterozygosity in the chromosome regions 3p and 11p in testicular tumors, these chromosome arms were paid special attention. However, no mutations were observed in these regions nor in any other chromosome. Applying a 95% confidence interval, we conclude that less than 23% of familial and/or bilateral testicular cancer patients are caused by germ line mutations large enough to be detected with high resolution banding of at least 450 G-bands per haploid genome. The presented analyses were used to standarize the resolution determination in our laboratory.

Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA class 1 sib-pair analysis

Forty-two families with two or more cases of testicular cancer have been reported to the UK Register for Familial Testicular Cancer, comprising two pairs of identical twins, 27 sets of other brothers (25 pairs, two triples), nine father-son pairs, two pairs of first cousins and two uncle-nephew pairs. In total 91 testicular tumours are described in 86 individuals (42 (46%) pure seminoma, 49 (54%) other germ cell tumours). The median age at diagnosis in these patients was significantly younger than that in a comparable series of non-familial patients (29 c.f. 32.5 years, P less than 0.01). In a case-control comparison of 794 testicular cancer patients, eight patients (1.0%) had a brother and four patients (0.5%) had a father with a previous diagnosis of testicular cancer at the time of their own diagnosis (and these families are all included in this report). Two out of 794 controls (0.3%) had a first degree relative with testicular cancer. The cumulative risk to a brother of a patient for developing testicular cancer by the age of 50 years was estimated to be 2.2% (95% C.I. 0.6-3.8%) which results in a relative risk of 9.8 (95% C.I. 2.8-16.7) in comparison with the general population. HLA Class I typing of 21 affected sib-pairs demonstrated four (19%) sharing two haplotypes, 13 pairs (62%) sharing one and four pairs (19%) sharing none. This did not differ significantly from the expected proportions of 25%/50%/25%. It is unlikely, therefore, that there is a major gene associated with testicular cancer predisposition within or closely linked to the major histocompatibility gene complex on chromosome 6.

High resolution karyotypes of lymphocytes from patients with bilateral or familial testicular cancer.

High resolution karyotypes of lymphocytes from patients with bilateral or familial testicular cancer.

No germ-line p53-mutations detected in familial and bilateral testicular cancer

No germ-line p53-mutations detected in familial and bilateral testicular cancer

Familial testicular cancer in five members of a cancer-prone kindred

Of a family of 13 siblings, four brothers have developed testicular neoplasms, one embryonal cell carcinoma and three testicular seminomas. A first cousin once removed on their mother's side of the family (fourth-degree relative) has developed an embryonal carcinoma. After treatment they are all alive and well. Their mother is a dizygous twin and one of ten siblings. Multiple other cancers have been diagnosed among her siblings and their offspring including breast carcinoma at age 30 years in monozygous twin nieces. Associated urogenital abnormalities, concordance of age, and discordance of pathology in the five males with testicular cancer is discussed. Further identification and reporting of this risk factor is encouraged.

Familial Testicular Cancer: Report of Six Cases and Review of the Literature

The cause of testicular cancer, like most other cancers, is unknown. Certain risk factors such as cryptorchidism, carcinoma in situ, and a preceding contralateral testicular germ cell neoplasm are known to predispose a person to the subsequent development of a testicular malignant lesion. Familial testicular cancer has been debated as a potential and possibly independent risk factor. Evidence in favor of such a hypothesis, based on various genetic studies reported during the past few decades, is reviewed. We add to the existing literature our experience with six cases of familial testicular cancer encountered during a 10-year period, consisting of four father-and-son pairs, one pair of nontwin brothers, and a 23-year-old man who had a maternal uncle with a history of testicular cancer.

Familial embryonal carcinoma in a cancer-prone kindred

Familial testicular cancer is rare. This report describes a family with an unusual cancer spectrum that included the infantile form of embryonal carcinoma of the testis in the son of a cancer-free but putative obligate gene carrier mother, and the adult form of embryonal carcinoma in this woman's maternal half-brother (their mutual mother had malignant melanoma and urinary bladder carcinoma). Hereditary syndrome designation remains elusive. Priority attention to biomarker research in families of this type for elucidation of cause and control Is discussed.

Familial testicular cancer and urogenital developmental anomalies.

In a case-control study of testicular cancer, 6 of 269 cases (2.2%) reported a first-degree relative with testicular cancer, compared to 1 of 259 controls (0.4%). Fathers and brothers of testicular cancer cases had a six-fold elevated risk of developing a testicular malignancy compared to men in the general population. Cryptorchidism was reported in a first-degree relative in 1 (17%) of the familial cases versus 7 of 259 (2.7%) controls and 14 of 263 (5.3%) cases with a negative family history for testicular cancer. One half of the 6 familial cases reported a first-degree relative with a groin hernia (all surgically repaired before age 12), compared to 12.7% of 259 controls and 10.3% of 263 nonfamilial cases. Three familial clusters identified through the case-control study were selected for clinical evaluation. One of the 6 surviving males with testicular cancer in these 3 families had undergone orchiopexy and inguinal herniorrhaphy at age 6 years, and one had a hydrocele associated with his testicular tumor. Of the 12 living fathers and brothers of these 6 men, 3 reported childhood inguinal hernias, two with coexisting hydroceles. One additional hernia and two additional hydroceles were detected during urologic evaluation of these healthy relatives. The high prevalence of cryptorchidism, inguinal hernias, and hydroceles among men in these families suggests that an underlying alteration in urogenital embryogenesis may be associated with the familial predisposition to testicular neoplasia.

Canine testicular tumors: Epidemiologic features of 410 dogs

Histologically confirmed testicular tumors were diagnosed in 410 dogs from 12 North American veterinary university hospitals and clinics. Three tumor-cell types, Sertoli cell tumor, interstitial cell tumor and seminoma, were about equally represented. Several breeds were identified with high risk for different testicular tumor-cell types. Cytogenetic and immunogenetic studies of these dog families could offer leads applicable to familial testicular cancer in man. The multiplicity of breeds within the series suggests that, as in man, other factors, in addition to hereditary, play a role in etiology. Cryptorchid dogs appear to have a 13.6 times higher risk of testicular tumor than normal dogs. Additionally, male dogs with an inguinal hernia have an increased risk (4.7) of testis tumors. There were no detectable excesses of other urogenital anomalies or urogenital tumors among the series. The Shetland Sheepdog is suggested as an appropriate model for research into the mechanisms responsible for testicular maldescent and tumorigenesis.