Infertility and testis cancer risk: causality or association?

In his state-of-the-art lecture, Prof. Leendert Looijenga discussed the connection between infertility and testicular cancer1. Both molecular associations and putative causality were reviewed.

In his state-of-the-art lecture, Prof. Leendert Looijenga (Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands) discussed the connection between infertility and testicular cancer1. Both molecular associations and putative causality were reviewed.

Testicular germ cell tumors (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 seven types of TGCTs, which can also be understood within terms of developmental processes.

Diagnosis, treating, and follow-up of TGCTs relies on an understanding of the disease’s biological drivers, yet little is really known. 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. 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 synchronized duplication using syncytia (=intercellular bridges) are characteristic of this spermatogonial stem cell compartment and there has been some speculation of 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.

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), said Prof. Looijenga.

Prof. Looijenga concluded that there is no effective way at the moment to tease out the cause and effect. 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 two conditions. The microenvironment may also be relevant, but reliable markers are still being developed to assay those effects.

1. Looijenga LH, et al. Infertility and the risk of testis cancer. EAU20 Virtual Congress, 17-26 July 2020, State-of-the-art-lecture.