Elsevier

European Journal of Cancer

Volume 42, Issue 12, August 2006, Pages 1869-1874
European Journal of Cancer

Re-analysis of the Xq27–Xq28 region suggests a weak association of an X-linked gene with sporadic testicular germ cell tumour without cryptorchidism

https://doi.org/10.1016/j.ejca.2006.03.009Get rights and content

Abstract

Background

A testicular germ cell tumour (TGCT) predisposing gene has been mapped to the Xq27 region on the X chromosome. These linkage findings remain to be confirmed by other studies.

Methods

In 276 patients and 169 unaffected first-degree male relatives, 12 microsatellite markers covering the candidate region were genotyped and used to study possible association of TGCT with Xq27.

Results

In contrast to previously reported linkage of familial TGCT and cryptorchidism with Xq27, we observed an association between the subset of TGCT cases without a family history of TGCT or cryptorchism and marker DXS1193 (p = 0.014). Carriers of minor alleles were at increased risk (odds ratio (OR) 4.7, confidence interval (CI) 1.1–19.6)

Conclusion

We found an association on Xq27 in a subset of TGCT cases, which suggests the presence of an X-linked gene that slightly or moderately increases risk to develop sporadic TGCT but not cryptorchidism.

Introduction

The incidence of testicular germ cell tumour (TGCT) is still rising.1 Although the aetiology of TGCT is poorly understood, it is well known that male relatives (fathers/brothers/sons) of TGCT patients have an increased risk of developing TGCT. Currently 1–3% of TGCT patients report an affected relative.2 Brothers of TGCT patients have an 8–10-fold increased risk of developing TGCT and the relative risk (RR) to fathers and sons is approximately 4–6.3, 4 Because these RRs associated with an affected first-degree relative are considerably higher than for other cancers, which rarely exceed four, this observation most likely points to a genetic role in the aetiology of TGCT.3

Efforts have been made to identify TGCT predisposing genes. Although TGCT families have been reported in the literature, multigenerational pedigrees with several affected cases are rare and this limits the opportunities for linkage studies. In 1994, the International Testicular Cancer Linkage Consortium (ITCLC) was formed with the aim to collect TGCT families from all over the world and to perform genotyping studies. Recently, Rapley and colleagues (on behalf of the ITCLC) presented evidence for a TGCT susceptibility gene on chromosome Xq27.5 Their genome-wide search for linkage in a set of 134 familial TGCT cases yielded a heterogeneity LOD (hlod) score of 2.01 on chromosome Xq27 using all families (n = 99) compatible with X-linked inheritance and a hlod score of 4.7 on chromosome Xq27, if they included only families with at least one bilateral TGCT case (n = 15) (genome wide significance level p = 0.034). In addition, 73% (n = 14) of the familial TGCT cases with a history of cryptorchism (synonymous with cryptorchidism), a well known risk factor for TGCT, were linked to locus Xq27. These results provided evidence for a gene on chromosome Xq27 involved in TGCT susceptibility as well as in cryptorchism. Two recombinations, one between markers DXS8043 and DXS8028 on the centromeric side and one between FRAXA.pcr2 and FMR1Di on the telomeric side, bounded the identified TGCT1 locus, resulting in an interval of ∼4 cM (∼2.7 Mb). In this region, two genes have been reported so far: FMR1, responsible for Fragile X syndrome and a single exon gene Cxorf1 (expressed in the brain).6 As yet, germline mutations in any gene in this region have yet to be identified as the cause of increased risk to develop TGCT.

An alternative approach to linkage studies is searching for TGCT susceptibility genes among unrelated TGCT cases in founder populations by means of association analyses on a dense set of markers. These so-called linkage disequilibrium fine-mapping analyses are based on the hypothesis that patients in founder populations inherited disease mutations from recent and common ancestors. A previous study showed geographic clustering of TGCT in the northern part of the Netherlands.7, 8 Another study presented the results of analyses of HLA microsatellite markers and TGCT in this founder population.9 The current study includes the previously used study population, expanded with additional TGCT patients from the same founder population. The aim of this study was to corroborate or refute the previously observed linkage between TGCT and chromosome Xq27 using association analysis and the haplotype sharing statistic (HSS).

Section snippets

Patients and controls

A total of 276 patients were randomly selected from all TGCT patients treated during the period 1977–2001 at the University Medical Centre Groningen (UMCG), The Netherlands. The majority of these patients descended from three provinces (Groningen, Friesland, and Drente) in the Northern Netherlands, based on information collected about birthplace of the patient’s great-grandparents. Histological diagnosis was established for all patients by the Department of Pathology of the UMCG.

Through the

Results

Of the 16 microsatellite markers that were genotyped, four did not meet our quality criteria (data not shown). Hence, the analyses were performed on the 12 markers shown in Table 2.

Allelic association analysis did not reveal any significant difference, i.e. p < 0.004, between general TGCT patients and controls at any marker (Fig. 1). In addition, the HSS did not show a significant result either (Fig. 2). As the sample of Rapley and colleagues5 consisted of familial TGCT cases and the linkage

Discussion

In the current study, we did not find an association between Xq27 and familial TGCT, cryptorchism or bilateral TGCT. We could therefore not confirm the results found by Rapley and colleagues.5 We should however notice that our subgroups of familial or bilateral cases or cases with cryptorchism were small, which results in sufficient power only when a disease mutation with a frequency of 5% (or higher) and the putative gene has a large effect (RR > 8 for cryptorchism; RR > 20 for bilateral or

Conflict of interest statement

None declared.

Acknowledgements

This work has been presented as a poster presentation at the American Society for Clinical Oncology (ASCO) annual meeting, 12–16 May, 2005. This research was supported by a Dutch Cancer Society Grant: RUG 1999-2130.

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