The Price of Human Evolution: Cancer-Testis-Antigens, the Decline in Male Fertility and the Increase in Cancer

Comment: Erenpreisa and colleagues wrote a stimulating article in Preprints.org, with an interesting evolutionary theory of growing problems with testis function, with focus on (patho)biology of germ cells and germ cell cancer. I enjoyed reading the paper. Big thanks to the authors!

I would like to indicate a mistake concerning their description of testicular germ cell tumours (TGCT), which should be corrected before the final publication. They apparently confused two different types of TGCT: seminoma and spermatocytic seminoma, and used an incorrect term “seminoma” to describe the latter. This confusion has been common in the past, so the WHO classification of testicular neoplasms was corrected in 2016 and introduced the new name ‘spermatocytic tumour’ (see Moch et al. 2016, PMID: 26935559), rendering the old term obsolete. Spermatocytic tumour is rare and the only germ cell-derived tumour that occurs exclusively in the adult testis and is usually diagnosed in men in their prime (median age around 50 y.). Among the features of spermatocytic tumour relevant for this article is a strong expression of CTA and spermatogonial survival promoting factors, and extensive aneuploidy (Giannoulatou et al. 2017 PMID: 28542371, and references therein). The vast majority of TGCT are derived from PGC/gonocyte-like germ cell neoplasia in situ (GCNIS), with numerous embryonic features, including pluripotency, and these tumours comprise seminoma and nonseminoma, see e.g. the cited review by Kristensen et al. 2008, #139 (PMID: 18420341) or a more recent excellent review by Oosterhuis & Looijenga 2019 (PMID: 31413324).
In Figure 4B, an imprecision in terminology of TGCT is propagated from otherwise excellent article of Florke Gee et al. 2020 (PMID: 32921631), who listed ‘seminoma’ with a high expression of MAGE genes. Figure 4C shows a summary of the subsequent analysis of the Mitelman karyotype database, and the term “seminoma” again is used. The authors most likely got hits for the ‘classical’ seminoma, derived from GCNIS. The Mitelman database lists not only ‘seminoma’ but also other types of TGCT, including teratoma (a subtype of nonseminoma) and combined germ cell tumours (seminoma + nonseminoma).
The confusion is evident in several places in the paper, but especially in section 8, in the paragraph starting from “To understand the situation with Testicular germ cell cancer …”, which contains several errors. It is incorrect that “the TGCT develops from (…) the PGC cells that does not even start the gonocyte/spermatogenesis pathway“ – GCNIS cells have features of transformed gonocytes (Sonne et al. 2009, PMID: 19491264), it is wrong to say that “TGCT does not express CT antigens” (some TGCTs do, some do not, heterogeneously) or “TGCT is very different from seminoma”. This part must be completely re-written.
I would like to emphasize that my comments concern only a minor part of the preprint and do not diminish its value in other aspects.