Infertility and testis cancer risk: causal or association?

In his state-of-the-art lecture, Prof. Leendert Looijenga (Princess Máxima Center for Pediatric Oncology, the Netherlands) discussed the connection between infertility and testicular cancer [1]. The molecular associations were reviewed as well as putative causality.

Testicular germ cell tumours (TGCTs) display a tremendous variety of morphologic elements, often in mixed pathologies. Generally, TGCTs are classified as either germ cell neoplasia in situ (GCNIS), or non-GCNIS-associated TGCTs. Most malignant TGCTs originate from GCNIS. Molecular and genetic studies have highlighted 7 types of TGCTs, which can also be understood within terms of developmental processes.

Diagnosis, treating, and follow-up of TGCTs relies on understanding of the biological drivers of the disease, yet little is really known. TGCTs originate from GCNIS precursors, which are characterised by expression of the markers OCT4, SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. Differentiation is regulated by gene-environment factors and stromal cell interactions. When OCT4 no longer represses AKT transcription, totipotency survival can promote polyploidisation, which is considered an early event in the formation of GCNIS, and ultimately lead to TGCTs (see Figure) [2].

Figure: Proposed model of TGCT development from GCNIS precursors [2]

GCNIS, germ cell neoplasia in situ; TGCT, testicular germ cell tumours.
Adapted from Cheng et al. 2018.

In patients with TGCTs, fertility preservation is an important component following cancer treatment, and the question posed here is whether infertility and TGCTs are causal or associated [1]. What we do know is that the GCNIS differentiation block of the spermatogonial stem cell is the earliest pathogenetic link between testicular carcinogenesis and infertility. The unique synchronised duplication using syncytia (=intercellular bridges) are characteristic of this spermatogonial stem cell compartment and there has been some speculation on the stability of those syncytia in promoting TGCTs and possibly fertility, which might be attributable to microtubule or centrosome stability at those sites. The cells would multiply at an undifferentiated state, and would not produce mature sperm in those instances.

Although a large number of studies support an association between infertility and TGCTs, causality has proven difficult to pin down. For example, a large and recent retrospective cohort study concluded that there was an increased risk of TGCT development in 20,433 men who had undergone semen analysis compared with 20,433 age- and birth year-matched fertile controls. In particular, men with oligospermia based on low concentration (HR 11.9; 95% CI 4.9–28.8) or low sperm count (HR 10.3; 95% CI 4.1–26.2) and infertile men with normozoospermia (HR 2.9; 95% CI 1.2–6.7) had an increased risk of testicular cancer [3].

Really novel in the field is that the microRNA miR-371a-3p is a putative molecular biomarker for TGCTs. The suspected mechanism is that all members of the miR-371-3 family inactivate P53, thereby disrupting cellular senescence. Furthermore, miR-371a-3p is expressed explicitly in all malignant components of TGCTs, either being type I or II, as well as being detectable in serum, plasma, and cerebrospinal fluids of patients with malignant TGCTs. There have been some reports that miR-371a-3p can serve as a robust molecular liquid biopsy TGCT biomarker, and is more informative compared with the trusted markers alpha fetoprotein (AFP) and/or the beta subunit of human chorionic gonadotropin (β-hCG). Prof. Looijenga concluded that there is no effective way at the moment to tease out the cause and effect currently; the complex effects of surgery, chemotherapy, and radiotherapy may contribute to infertility, particularly in those at elevated risk of baseline subfertility or infertility, but it is essential to assume that there may be connected aspects of these 2 conditions. The microenvironment may also be relevant, but reliable markers are still being developed to assay those effects.

1. 1. Looijenga LH, et al. EAU20 Virtual Congress, 17-26 July 2020, State-of-the-art-lecture.
   2. Cheng L, et al. Nat Rev Dis Primers 2018;4, 29.
   3. Hanson HA, et al. Fertil Steril. 2015;105(2):322-8.e1.

Posted on 24 August, 20205 August, 2021