Approximately 95 percent of malignant tumors arising in the testis are germ-cell tumors, a term that indicates their origin in primordial germ cells. Germ-cell tumors also occasionally arise in extragonadal primary sites, and their management follows that of testicular germ-cell tumors. More than 90 percent of patients with newly diagnosed germ-cell tumors are cured, and delay in diagnosis correlates with a higher stage at presentation for treatment.1,2 Management has changed substantially in the past 20 years, largely because of the ability of cisplatin-containing combination chemotherapy to cure advanced disease.3 In this review, we discuss recent developments in our understanding . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199707243370406

Testicular Germ-Cell Cancer

REVIEW ARTICLE Genomewide Scans of Complex Human Diseases: True Linkage Is Hard to Find

Testicular germ-cell cancer

Many "complex" human diseases, which involve multiple genetic and environmental determinants, have increased in incidence during the past 2 decades. During the same time period, considerable effort and expense have been expended in whole-genome screens aimed at detection of genetic loci contributing to the susceptibility to complex human diseases. However, the success of positional cloning attempts based on whole-genome screens has been limited, and many of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. Both to review the success of the positional cloning paradigm as applied to complex human disease and to investigate the characteristics of the whole-genome scans undertaken to date, we created a database of 101 studies of complex human disease, which were found by a systematic Medline search (current as of December 2000). We compared these studies, concerning 31 different human complex diseases, with regard to design, methods, and results. The "significance" categorizations proposed by Lander and Kruglyak were used as criteria for the "success" of a study. Most (66.3% [n=67]) of the studies did not show "significant" linkage when the criteria of Lander and Kruglyak (1995) were used, and the results of studies of the same disease were often inconsistent. Our analyses suggest that no single study design consistently produces more-significant results. Multivariate analysis suggests that the only factors independently associated with increased study success are (a) an increase in the number of individuals studied and (b) study of a sample drawn from only one ethnic group. Positional cloning based on whole-genome screens in complex human disease has proved more difficult than originally had been envisioned; detection of linkage and positional cloning of specific disease-susceptibility loci remains elusive.

http://www.alliot.fr/BIO/PDF/AJHGv69p936.pdf

Genomewide Scans of Complex Human Diseases: True Linkage Is Hard to Find

Purpose: Testicular cancer (TC) is the most common malignancy in 20 to 34-year-old men. Numerous publications have shown an increase in the incidence of testis cancer in the last 40 years with substantial differences among countries. We evaluated worldwide variations in testicular cancer incidence and compared trends in different regions in the world. Materials and Methods: We reviewed 441 studies provided by a MEDLINE search using the key words testis/testicular, cancer/tumor and incidence that were published between 1980 and 2002. From these articles we selected only those devoted to testis cancer incidence and of them only the most recent studies from each country or region. Nevertheless, articles using the same data base but providing new and additional information, for example differences among ethnic groups or controversial explanations for trends, were also retained. We selected 30 articles and analyzed their methodological approach and main results. Results: Worldwide we observed a clear trend toward an increased TC incidence in the last 30 years in the majority of industrialized countries in North America, Europe and Oceania. Nevertheless, surprising differences in incidence rates were seen between neighboring countries (Finland 2.5/100,000 cases versus Denmark 9.2/100,000) as well as among regions of the same country (2.8 to 7.9/100,000 according to various regional French registers). In addition, substantial differences in the TC incidence and trends were observed among ethnic groups. The increase in the TC incidence was significantly associated with a birth cohort effect in the United States and in European countries. To date except for cryptorchidism no evident TC risk factor has been clearly demonstrated, although the environmental hypothesis with a key role of endocrine disrupters has been put forward by several groups. Conclusions: Such a recent increase in the TC rate in most industrialized countries should lead urologists and andrologists to give more attention to testicular cancer symptoms in adolescents and young adults. In a public health perspective further research using cases collected through national and regional population based registers and case-control studies must be strongly encouraged if we wish to be able to assess future trends in TC incidence rates and also identify risk factors.

Review Article INCREASING INCIDENCE OF TESTICULAR CANCER WORLDWIDE: A REVIEW

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.

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

Epidemiological data suggest the presence of a susceptibility gene for testicular cancer in some families. Families with multiple cases of testicular cancer are rare and almost all those reported have only two affected members. We have performed a sib-pair analysis on 35 families in which there are either two or three affected brothers. These families have been typed for 220 autosomal microsatellite markers spaced 10-20 cM throughout the genome. Six regions which gave a LOD score of more than 1.0 on formal linkage analysis or a P value of 0.05 or less using a non-parametric approach are considered as candidate regions for a susceptibility gene. Of particular interest is one region on chromosome 4. Two neighbouring probes in this region both scored positively with LOD score of 2.60 on multipoint analysis. An International Testis Cancer Linkage Consortium has been formed to pool resources and will investigate these findings further with the world-wide collection of families.

D. Forman

Papers

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

Candidate regions for a testicular cancer susceptibility gene