Testicular cancer accounts for only 1 % of all malignancy in males (with an incidence of 4 per 100,000 males) but is the most frequent carcinoma in the 15–35-year age group. Most Tumours are of germ cell origin (seminoma, teratoma) but some arise from stromal cells (Sertoli cell), and gonadoblastoma contains germ cell and stromal elements.
Familial aggregation of testicular germ cell Tumours accounts for up to 2 % of all adult cases. In a literature review, 24 father-son pairs, 45 pairs of non- twin brothers and 12 pairs of identical twins with testicular cancer were cited. Tumours are of the same histological type in 70 % of identical twin pairs but were mostly of different histology in other degrees of relationship. Testicular Tumours are bilateral in about 4 % of patients, which is suggestive of a genetic basis. In a Dutch single-centre study, RR of testicular cancer was increased 9- to 13-fold in brothers (Sonneveld et al. 1999). In an analysis of the Swedish Family-Cancer Database, familial risks were increased to 3.8-fold for fathers, 8.3-fold for brothers, and 3.9-fold for sons, and although seminomas showed a later age at onset than teratomas (30 versus 40 years), the familial risks were similar for the two Tumours types (Dong et al. 2001). Forman et al. (1992) found that brothers of men with testicular cancer had a 2 % risk of developing testicular cancer by the age of 50 years, which corresponds to a 10-fold increase in RR. The mean age at diagnosis in familial cases was slightly younger than in sporadic cases (29.5 years versus 32.5 years).
Large families with a high incidence of testicular cancer have been described but are rare: Lynch and Walzak (1980) studied a large inbred Dutch kindred in which four individuals had histologically proven testicular
cancers, and Goss and Bulbul (1990) reported a large cancer-prone family (including early-onset breast cancer) in which five males had testicular cancer. Nicholson and Harland (1995) and Heimdal et al. (1997) have suggested that familial clustering of testicular cancer might be attributable to a recessive gene. However, familial testicular cancer appears to be genetically heterogeneous, and an X-linked locus has been mapped.
The principal risk factor for testicular cancer is cryptorchidism, which is associated with at least a 10-fold increase in risk, and orchidopexy should be performed in early childhood for boys with cryptorchidism if this risk is to be diminished. Genetic factors have been implicated in cryptorchidism because up to 14 % of cryptorchid males have an affected relative, but it is unclear to what extent this might explain the familial occurrence of testicular Tumours.
Patients with X-linked ichthyosis (steroid-sulfatase deficiency) appear to be at increased risk of cryptorchidism and testicular Tumours. Testicular microcalcification is also a risk factor (Coffey et al. 2007).
Klinefelter syndrome has rarely been reported to predispose to testicular Tumours, but in some cases this may be related to cryptorchidism. In one case, however, bilateral testicular teratoma occurred in a sib pair with Klinefelter syndrome. The risk of testicular cancer (seminoma, Sertoli cell, teratocarcinoma, and embryonal cell carcinoma) is unequivocally increased in patients with the testicular feminization syndrome, and prophylactic gonadectomy is usually performed after pubertal growth. Gonadoblastoma occurs in XY gonadal dysgenesis, and also in patients with the WAGR syndrome (Wilms Tumours–aniridia–genital abnormality–mental retardation). A subclass of Sertoli cell Tumours (large cell calcifying) can be familial and can be associated with cardiac myxoma, endocrine activity, and pigmented skin lesions in Carney complex. Similar testicular lesions (intratubular large cell hyalinizing Sertoli cell Tumours) are also seen in Peutz–Jeghers syndrome where they often present with gynecomastia (Ulbright et al. 2007).
Chromosomal analysis of germ cell testicular Tumours has implicated isochromosome of 12p as a specific finding. Although various associations between HLA haplotypes and testicular cancer have been proposed, HLA class I analysis of affected sib pairs provided no evidence of a HLA-linked testicular cancer susceptibility gene. However, Rapley et al. (2000) mapped a locus for testicular germ cell Tumours (TGCT1) to Xq27 using families compatible with X inheritance. Cases linked to Xq27 were more likely to have undescended testis and bilateral disease. There was clear evidence of locus heterogeneity and autosomal susceptibility loci are likely.
More recent data suggests that no one single locus can account for a significant fraction of familial testicular Tumours (Crockford et al. 2006). Interestingly, a Y-chromosome locus involved in infertility known as the “gr/gr” deletion is a rare, low-penetrance susceptibility allele for testicle Tumours (particularly seminomas) with a population frequency of n0.013 and an odds ratio of 3.0 for seminoma (P = 0.0004). Genome-wide association studies have identified low-penetrance variants in six loci, implicating KITLG, SPRY4, and BAK1 (all involved in the KIT/KITL pathway), TERT and ATF7IP (both involved in telomerase regulation), and DMRT1 (involved in sex determination) in Tumoursigenesis (Kanetsky et al. 2009; Rapley et al. 2009; Turnbull et al. 2010). The six loci, together with the “gr/gr” deletion account for less than 15 % of the familial risk of TGCT, which implies that potentially many more risk alleles remain to be identified. The clinical utility of testing for these alleles is therefore currently limited.
The occurrence of testicular Tumours in high-risk individuals can be prevented by appropriate measures. Cryptorchidism should be corrected early to avoid an increased risk of testicular Tumours. Nonfunctioning testes that present a significant risk for Tumoursigenesis (as in the testicular feminization syndrome or intersex states) should be removed. Individuals thought to be at high risk of familial testicular Tumours can be monitored by regular self- examination and ultrasonography.