Translating Testicular Cancer Epidemiology into Clinical Practice

In this issue of European Urology, Kharazmi and colleagues [1] report an elegant epidemiological analysis of pooled data from five Nordic countries to describe both the absolute and relative risk of testicular cancer in family members of affected individuals. The study confirms findings from prior studies revealing similar relative risk estimates among family members of subjects with testicular cancer [2]. Interestingly, and importantly, however, the study offers the reader estimates of absolute risk that will, undoubtedly, facilitate the use of these data in clinical practice. This study certainly answers questions surrounding estimation of testicular cancer risk in families; however, it also highlights other questions that remain unanswered, including: (1) how do these data fit within contemporary theoretical frameworks of testicular cancer etiology, specifically with respect to the likely complex interplay between genetics and environment? and (2) how might we, as clinicians, translate these research findings into clinical practice? There is increasing evidence that invasive germ-cell tumors nearly universally arise from intratubular germ cell neoplasia (ITGCN), a noninvasive precursor lesion found in association with approximately 90% of invasive germ-cell tumors thought to arise antenatally [3,4]. Subsequent mutations and epigenetic changes, in the context of hormonal changes at puberty, may then result in transformation of ITGCN to invasive testicular cancer [5]. How, then, do the data presented by Kharazmi et al fit within this theoretical framework regarding the etiology of testicular cancer? The fourfold increase observed among brothers of affected individuals translates to an absolute cumulative risk of only 2.3%, indicating a considerable degree of heterogeneity with respect to disease development despite presumed genetic risk. Not surprisingly, the risk of incident testicular cancer in twin brothers was found to be higher, possibly lending additional support to the transmission of genetic risk. Unfortunately, this study does not permit the reader to untangle the complex relationships between genetics and environment. There remains considerable uncertainty regarding the precise etiology of in utero development of ITGCN. While identical twins share their genetic complement, they also share fetal exposures, rendering identification of the precise contribution of genetics and environmental exposures to the development of ITGCN a challenge. Beyond the development of ITGCN, however, there remains a significant knowledge gap regarding risk factors for the development of invasive testicular cancer. It is well known that ITGCN is a significant risk factor for the development of invasive disease, with an estimated 50% risk of testicular cancer within 5 yr. Nonetheless, not all men with ITGCN will develop testicular cancer, and even though numerous groups have identified candidate genes and epigenetic changes involved in the transformation of ITGCN to invasive disease, the etiology of this transformation remains poorly understood. In the current study, the authors report greater than threefold between-country variation in the risk of testicular cancer among brothers of affected individuals. While this finding may result from the relative rarity of testicular cancer or variation in the fidelity of data collection between registries, it is also possible that the variation reflects variation in the environmental attributes contributing to the development of testicular cancer.