Cryptorchidism and Testicular Tumor: Comprehensive Analysis of Common Clinical Features and Search of SNVs in the KIT and AR Genes

Daniel Adrian Landero-Huerta,Elena Aréchaga-Ocampo,Rosa María Vigueras-Villaseñor,Margarita Dolores Chávez-Saldaña,José Díaz-Chávez,Julio César Rojas-Castañeda,Fabiola García-Andrade,Luis Alonso Herrera-Montalvo,Isidro Xavier Pérez-Añorve,Emiy Yokoyama-Rebollar

doi:10.3389/fcell.2020.00762

Abstract

Allelic variants in genes implicated in the development of testicular germ cell tumor (TGCT) could be present in patients with cryptorchidism (CO). Currently; the mechanisms explaining this relationship are still unknown. In this study the common clinical features in patients with CO and TGCT and 6 variants of KIT and AR genes associated to TGCT were analyzed. Population analyzed included 328 individuals: 91 patients with CO; 79 with TGCT, 13 of them with previous CO diagnosis, and 158 healthy males. Of the 13 patients with TGCT and history of CO, one patient (7.7%) presented the heterozygous form of the variant rs121913507 and two patients (15.4%) presented homozygote genotype for the variant rs121913506 in KIT gene. Interestingly, the heterozygous form for the variant rs121913506 of KIT gene was identifying in all of 13 patients. The rs201934623, rs774171864, and rs12014709 variants of the AR gene did not show any clinical association. Our results strongly support that genetic component in CO could be conditioning for the development of TGCT. Notably, KIT gene variants might be determinants in the pathological association between TGCT and CO.

Highlights

Cryptorchidism (CO) or undescended testis (OMIM#219050), is the most common genitourinary malformation in newborn males
Studies that have been focused on searching diagnostic markers for testicular germ cell tumor (TGCT) proposed several single nucleotide variants (SNVs) in genes such as POU5F1, DND1, kinase receptor (KIT), KITLG, androgen receptor (AR), DMTR1, SPRY4, BCL2, NANOG, TGFBR2, PTEN, AKT1, PDE11A, GATA4, and THOC1 (Dalgaard et al, 2011; Turnbull and Rahman, 2011; Landero-Huerta et al, 2017; Litchfield et al, 2017)
We identify 4.5% patients with TGCT without CO (3/66) with at least one family member affected by the same neoplasm, and a global frequency of 3.8% (3/79 patients with TGCT), these were according to other authors for familiar TGCT (Mai et al, 2009; Rapley and Nathanson, 2010); we observed higher frequency of nsTGCT in our patients with TGCT, similar to Hispanic population (Woldu et al, 2018; Table 1)

Summary

Introduction

Cryptorchidism (CO) or undescended testis (OMIM#219050), is the most common genitourinary malformation in newborn males. It has not been shown that genetic variants in these genes are responsible for causing CO or Germ cell neoplasia in situ (GCNIS) a precursor lesion to TGCT, both genes have a role in testicle development and testicular carcinogenic process, influencing directly as in the case of AR, through nongenomic pathways (Walker, 2003). The KIT gene codifies a class III homodimeric receptor with tyrosine kinase activity in humans. Receptor and ligand are essential for survival, migration and differentiation of the early germ cells (gonocytes; Sheikine et al, 2012). Gonocytes have been proposed as responsible for the development of GCNIS (Vigueras-Villaseñor et al, 2015; Berney et al, 2016). AR is overexpressed in GCNIS and it has been found in gonocytes unable to differentiate properly (Merlet et al, 2007)

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