Epidemiology and Risk Factors for Testicular Cancer: A Systematic Review - Beyond the Abstract
Conversely, regions like Asia and Africa have traditionally reported lower incidences but are now experiencing significant increases. For example, Japan, Thailand, and Korea have seen annual percentage changes of 6–8%, suggesting an epidemiological shift. This disparity highlights the influence of genetic predisposition but also socioeconomic factors. Indeed, the higher incidence is observed in regions with higher human development indices, raising critical questions about the role of industrialization, lifestyle changes, and environmental exposures in determining TGCT risk. Migration studies also underscore how shifting environmental and cultural contexts may alter generational risk.
In our review we highlighted the role of polygenic predisposition, with single-nucleotide polymorphisms (SNPs), accounting for 44% of TGCT heritability. Genome-wide association studies have identified 78 susceptibility loci, with some linked to key pathways in germ cell development and chromosomal stability. Among these, the KITLG rs4474514 variant demonstrates the strongest association. Men with polygenic risk scores in the 95th percentile have a 6.8-fold increased risk of TGCT compared to the general population. Familial clustering further supports the genetic basis of TGCT, as first-degree relatives of TGCT patients face a 4- to 8-fold higher risk, and there is an enrichment for TGCT risk SNPs in familial cases.
Cryptorchidism remains the strongest perinatal factor, associated with a 4-fold increased risk, particularly when orchidopexy is delayed beyond the first year of life. Moreover, prenatal exposure to endocrine-disrupting chemicals (EDCs) such as pesticides has been implicated in TGCT risk. Maternal exposure to EDCs seems to double the risk of TGCT in offspring, with stronger associations for nonseminomas. Additional prenatal factors, such as parental occupational exposures, show weaker associations. The testicular dysgenesis syndrome hypothesis proposes that disrupted testicular development during embryogenesis could link cryptorchidism, infertility, and TGCT, although this theory is debated.
Infertility and subfertility are strongly linked to TGCT, with infertile men having nearly twice the risk. Additionally, high height, probably influenced by early-life growth factors, has been consistently associated with TGCT risk. Environmental and occupational exposures also warrant attention. Professions involving exposure to carcinogens, such as firefighting and industrial work, have been also linked to TGCT. Similarly, behavioral factors like marijuana use, processed meat consumption, and the use of muscle-building supplements show associations with TGCT risk.
To strengthen the evidence of our systematic review we conducted a meta-analysis on prenatal, perinatal, and postnatal risk factors for TGCT. Of 53 studies included in the systematic review, 26 were eligible for quantitative synthesis. The stronger results were observed for prenatal and early-life factors, showing a significant 44% increased TGCT risk (OR: 1.44, 95% CI: 1.17–1.78), rising to 56% (OR: 1.56) after outlier removal. Despite limitations, such as heterogeneity and observational design of included studies, our analysis strongly underscores the critical role of early-life and environmental factors in TGCT pathogenesis.
The interplay between genetic predisposition and environmental exposures remains a critical focus in TGCT research. While genetic factors may determine baseline risk, environmental exposures appear to modulate this risk across generations. Migratory studies corroborate this point, revealing that first-generation immigrants retain lower TGCT incidence rates of their original countries, while second-generation immigrants acquire the risk profile of the host country. To improve our knowledge, it is fundamental to bridge the research gaps across diverse populations. Indeed, most GWAS data are derived from European ancestry, not covering other ethnicities. Moreover, the role of socioeconomic changes requires targeted investigation. To face the global rising burden of TGCT, advancing our understanding of TGCT etiology is essential for identifying modifiable risk factors and improving early detection, with preventive measures and screening programs tailored to high-risk groups.
Written by: Valentina Tateo, MD, Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
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