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• W2960491972 abstract "It is my great pleasure to introduce to our readers this special issue devoted to testicular germ cell cancer. This is the second special issue on this topic published in Andrology, following one published 4 years ago (Rajpert-De Meyts et al., 2015). Most of the articles were kindly provided by the lecturers at the 9th Copenhagen Workshop on Testicular Germ Cell Cancer, held in Denmark in October 2018. Some of these papers include interesting comments that followed plenary lectures. In addition to the Copenhagen Workshop proceedings, the journal had an open call for papers on testicular cancer. All contributions – those solicited and those submitted independently – have been rigorously peer-reviewed, according to the standards of Andrology. Like the previous edition, this one covers basic, translational and clinical aspects of testicular cancer, and will be of interest to a multidisciplinary audience, including reproductive biologists, andrologists, pathologists, urologists, oncologists, geneticists and epidemiologists. Testicular cancer is nearly synonymous with testicular germ cell tumours (TGCT), which are – by far – the most common malignancies occurring in the testis. Hence, only TGCT are covered in this issue, and I highlight here some contributions, in the context of recent developments in clinical and basic aspects of testicular cancer. The changing trends in the incidence of testicular cancer worldwide have fascinated at least two generations of epidemiologists. The overall trend is the increasing incidence, with recent unexplained spikes in Southern Europe and American Hispanic populations (Trabert et al., 2015). On the other hand, in some countries, especially in Northern Europe that historically had the highest rates of testicular cancer, there are now clear signs of abating, as also shown in Germany in a study published in this issue (Brandt et al., 2019). In contrast to populations of European descent, African and East Asian ethnicities have markedly lower incidence rates of testicular cancer and appear to be protected, most likely due to the different constellations of susceptibility genes. There are some interesting exceptions, for example in New Zealand, where testicular cancer incidence is higher among the Maori than in the white population (Gurney, 2019). The trends in New Zealand are a good example of the complex interplay between genetic predisposition and yet unknown environmental/lifestyle factors in the pathogenesis of testicular cancer, which is a focus area still in need of further research. Testicular germ cell tumours are most common in young men, with the peak incidence around the age of 30–35, which is the age when men seek help for fertility problems. Hence, andrologists and specialists performing diagnostic work-up in infertile couples should be aware of testicular cancer, especially the pre-invasive early stage; germ cell neoplasia in situ (GCNIS), previously known as carcinoma in situ (Skakkebaek, 1978; Berney et al., 2016). It is important to bear in mind an increased risk of GCNIS or TGCT in patients with poor semen quality and testicular atrophy, a history of cryptorchidism or other genital malformations, all components of the testicular dysgenesis syndrome (Skakkebaek et al., 2003). It follows that these patients have decreased testis function and semen quality even before the diagnosis of malignancy. Two studies in this issue looked closely at the semen parameters in patients with TGCT. A large clinical study from a semen bank confirmed that TGCT patients had decreased sperm concentration and total motile sperm count even before treatment (Xu et al., 2019). Similar findings are reported in another translational study, which followed these observations by comparing the proteomic profiles of spermatozoa from testicular cancer patients with asthenozoospermia and normospermia, and found quantitative changes in several proteins involved in mitochondrial function, oxidative phosphorylation and fertilisation (Panner Selvam et al., 2019). Testicular function usually gets worse after treatment for testicular cancer, so the patients must be carefully followed for signs of hypogonadism and associated co-morbidities (Sprauten et al., 2014; Bogefors et al., 2017). Impaired function of Leydig cells is usually manifested by decreased testosterone and increased serum LH levels and often by the presence of large Leydig cell clusters in testicular biopsies (Tarsitano et al., 2018). An interesting longitudinal study in this issue examined the utility of INSL3 as a possible marker of Leydig cells function and predictor of hypogonadism in testicular cancer survivors (Steggink et al., 2019). The authors measured serum gonadotrophins, testosterone and INSL3 levels in patients with or without hCG-producing TGCT, who had been treated either by orchiectomy alone or surgery and chemotherapy. The INSL3 levels reflected mainly the number of Leydig cells (halved by orchiectomy) and returned to normal levels after two years of follow-up but did not correlate with hypogonadism or other late effects of chemotherapy (Steggink et al., 2019). With regard to diagnostic markers, progress has been made in developing microRNA (miR)-based assays for malignant germ cell detection in blood and semen samples. The assay is based on the high expression of miR-371a-3p in malignant germ cells, which reflects their similarity to embryonic stem cells (Gillis et al., 2013). Unexpectedly, miR-371a-3p has been also found in semen samples from healthy men without malignancy, thus questioning the specificity of this assay for detection of GCNIS cells. The source of miR-371a-3p in normal adult men is an important question, which was addressed by two studies in this issue. One study examined systematically all elements of the male urogenital tract that can contribute microRNA to ejaculate and demonstrated that miR-371a-3p in healthy men is solely derived from germ cells, with levels correlating to some extent with sperm concentration (Boellaard et al., 2019). The other study also detected miR-371a-3p in seminal fluid of men without TGCT and found positive correlation with sperm concentration and total sperm count (Radtke et al., 2019). Although it remains to be sorted out which types of germ cells secrete the miR-371a-3p and in which maturation stage the levels are highest, the findings of the two studies open a possibility of using the miR-371a-3p as a novel biomarker for stages of spermatogenesis in patients with infertility. Recent years brought a significant progress in the understanding of the genomic features of TGCT, thanks to genome-wide association studies (GWAS) and large whole-genome sequencing (WGS) studies. These studies provided evidence for a complex polygenic nature of TGCT, with a large number of variants responsible for the heritable risk, and the latest findings are nicely summarised in this issue (Lafin et al., 2019). In addition, an interesting original study addressed the hypothesis that a higher risk of TGCT in the brothers than in sons of cases could be due to recessively acting genetic susceptibility factors and refuted this by excluding the presence of excessive homozygosity in the genome (Loveday et al., 2019). Specific oncogenic driver mutations have not been identified in TGCT, and there is a striking paucity of recurrent somatic mutations, except for KIT, KRAS and NRAS mutations, identified mainly in seminomas (Shen et al., 2018). KIT- and RAS signalling and other possible pathways indicated by GWAS to be involved in TGCT pathogenesis have been reviewed in two articles in this issue (Das et al., 2019; Lafin et al., 2019). Among the special genomic features of TGCT, large chromosomal abnormalities, such as pathognomonic amplification of 12p, known for decades, have been confirmed by more recent WGS studies (Taylor-Weiner et al., 2015). These aberrations, with segmental copy-number variations and polyploidy, are suspected to be linked to the inherent features of the biology of the TGCT cell of origin; germ cell, which is the only cell type using two mechanisms of cell division, including a specific mechanism of meiosis. Dysfunction of the mitosis-meiosis switch during foetal development has been proposed as one of the possible mechanisms of the GCNIS initiation, and incomplete activation of some meiosis genes was reported in GCNIS (Jørgensen et al., 2013). A new study examined DMRT1 and DMRTB1, transcription factors implicated in the negative regulation of the mitosis-meiosis switch, and detected DMRTB1 in a small subset of PLAP-OCT4+ GCNIS cells (Hilbold et al., 2019). The intriguing dynamics of the mitosis-meiosis transition in malignant germ cells and its correlation with chromosomal changes and polyploidisation requires more research to elucidate. The current state of knowledge is reviewed by Feichtinger & McFarlane in this issue. Interestingly, aberrant activation of meiotic genes has also been detected in other types of cancers, suggesting that some germ cell-specific mechanisms can be inherently oncogenic, as explained in this excellent review article (Feichtinger & McFarlane, 2019). It is important to remember that germ cells significantly change their inherent functional machinery while maturing from primordial germ cells to haploid gametes. One of the mechanisms involved is the DNA repair system, which differs in embryonic germ cells in comparison with adult germ cells and somatic cell types. As reviewed in this issue (Bloom et al., 2019), embryonic germ cells do not activate DNA damage response and are prone to apoptosis, which partly explains their exquisite sensitivity to cytotoxic treatment. Resistance to chemotherapy, especially the commonly used cisplatin, is one of the most serious problems in the management of patients with TGCT, because the repeated failure of chemotherapy gives very poor prognosis for survival. Research efforts have been directed to improve our understanding of the mechanisms of chemoresistance, including studies of the genomic features associated with resistance (Taylor-Weiner et al., 2016). More differentiated TGCT are less chemosensitive, hence studies of the regulation of pluripotency in early germ cells and TGCT-derived cell lines, with focus on epigenetic factors, for example inhibitors of DNA methylation, have led to development of new, promising treatments (Albany et al., 2017). An excellent review of the current epigenetic-based approaches to overcome cisplatin resistance is included in this issue (Oing et al., 2019). Another novel approach to treat patients with recurrent or chemoresistant TGCT is immune therapy (Chovanec et al., 2019). The testis is a very special organ because of immune privilege of the seminiferous epithelium. However, infiltration by inflammatory cells is common in patients with infertility and with germ cell malignancy, suggesting disruption of immune surveillance. These aspects, as well as the immune response to chemotherapy, and the latest results of first immunotherapy trials with compounds targeting PD-1/PD-L1 pathway in genitourinary cancers are reviewed in detail in this issue (Chovanec et al., 2019). Finally, I use this opportunity to sincerely thank all authors for their excellent work that made this issue truly special. Multidisciplinary and collaborative efforts in recent years have clearly improved our understanding of the pathogenesis of testicular cancer but this disease remains an enigma in many aspects especially the environmental aetiology. We also need to further improve post-treatment health and quality of life of the survivors. Hence, I invite all our readers to continue working on topics related to testicular cancer, one of the few quintessentially andrological malignancies. The author thanks the Scientific Programme Committee of the 9th Copenhagen Workshop on Germ Cell Cancer: Gedske Daugaard, Niels E. Skakkebæk, Kristian Almstrup, Anne Jørgensen, Niels Jørgensen, and Katherine Nathanson. Many thanks to members of the Local Organising Committee: Kathrine Hurtigkarl, Tine Kerff Michelsen, Britt Marie de Stricker and Anders Juul. Special thanks go to Dr Ken Grigor for his expert editing of the meeting comments and great contribution to the social events. All Workshop organisers gratefully acknowledge a very generous meeting grant from the Novo Nordisk Foundation (Denmark) which made the Copenhagen Workshop possible. We also acknowledge help from other supporters: Society for Reproduction and Fertility (United Kingdom), the University of Otago (New Zealand), and the European Academy of Andrology (EAA)." @default.
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• W2960491972 title "Testicular germ cell cancer: recent developments in biology and clinical management" @default.
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