Y chromosome haplotypes and testicular cancer in the English population.

Testicular cancer (TC) affects 1 in 500 males and is the most common malignancy among young men in western European populations; for example, in Denmark 1% of all men now develop TC. More than 97% of testes cancers are germ cell tumours. Although the aetiology of these malignancies is unknown, there is accumulating evidence of an intrauterine stage of TC development that may involve both environmental and genetic factors acting on the primordial gonocyte. Although many tumour suppressor genes have been studied, there is little evidence supporting a role for these factors in the pathogenesis of TC. A number of epidemiological studies suggest that hypospadias, cryptorchidism, testicular cancer, and male infertility may share, in part, a common aetiology and this has given rise to the term “testicular dysgenesis syndrome”. TC is associated with poor spermatogenic function and recent data indicate that this dysfunction is associated with impaired infertility several years before diagnosis. Spermatogenic dysfunction is more common than can be explained by either local tumour or general cancer effect, since patients with other malignant diseases have normal, or only slightly decreased, semen quality. Human Y chromosome loss and rearrangements have been associated with specific types of cancer, such as bladder cancer, male sex cord stromal tumours, lung cancer, and oesophageal carcinoma, suggesting that both oncogenes and tumour suppressor genes exist on this chromosome. A number of Y chromosome genes, or gene families, appear to be necessary for male germ cell development and maintenance 13 and are candidates for involvement in oncogenesis of male specific cancers. Indeed, a cancer predisposition locus has been assigned to this chromosome, the gonadoblastoma locus (GBY). The location, function, and expression profile of the testis specific protein Y gene (TSPY) in germ cell tumours, prostate tumours, and normal tissue suggest that it is an excellent candidate for the GBY gene. Also, the loss and gain of Y chromosome material and differential expression of some Y genes was reported in prostate cancers, reinforcing a role for the Y chromosome in malignancy and cancer progression. Y chromosome lineages are highly geographically stratified among human populations. The variation of the nonrecombining region of the Y chromosome (NRY) has been successfully used to study human origins and population histories, 22 based on the assumption that Y chromosome variation is selectively neutral. However, if selection occurs, the majority of the Y chromosome will be affected, and not just single genes, given the absence of recombination. An increased (or decreased) frequency of a particular Y lineage in the affected population may unmask the presence of a functional variant, in linkage with the neutral mutation defining the haplogroup. In this context, the choice of the control population is critical, since statistical differences in haplogroup frequencies between the affected and control populations may be caused by population related factors (for example, population substructure) and not by an actual association with the phenotype under study. Several associations have already been reported between Y chromosome lineages and various phenotypes, such as protection against Y chromosome transfer to the X chromosome leading to XX-Y maleness, high blood pressure, and alcoholism. Conversely, absence of correlation has been reported between Y variation and some behavioural disorders, such as autism and personality traits related to alcohol dependence. Recently, an association between Y background and reduced sperm counts has been reported in Japanese and Danish populations. In Denmark, a specific class of Y chromosomes, hg26+, is associated with reduced sperm counts (<20 × 10/ml), although the underlying molecular cause of this reduction remains undefined. It is conceivable that Y encoded factors, involved in germ cell maturation, are implicated in the progression of TC. The purpose of this study was to analyse the effects of the Y chromosome background in testicular tumour formation. To assess Y chromosome differences, seven unique event polymorphism (UEP) markers and six microsatellites were used to construct Key points