Testicular Cancer


Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (69)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

MDM2 12q15 HDMX, hdm2, ACTFS -MDM2 and Testicular Cancer
DROSHA 5p13.3 RN3, ETOHI2, RNASEN, RANSE3L, RNASE3L, HSA242976 -DROSHA and Testicular Cancer
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Testicular Cancer
SPRY4 5q31.3 HH17 -SPRY4 and Testicular Cancer
CYP19A1 15q21.2 ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM -CYP19A1 and Testicular Cancer
PTEN 10q23.31 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN and Testicular Cancer
TOP1 20q12 TOPI -TOP1 and Testicuar Cancer
DNMT3B 20q11.21 ICF, ICF1, M.HsaIIIB -DNMT3B and Testicular Cancer
XIST Xq13.2 SXI1, swd66, DXS1089, DXS399E, LINC00001, NCRNA00001 -XIST and Testicular Cancer
CDK4 12q14.1 CMM3, PSK-J3 -CDK4 and Testicular Cancer
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2 -PDGFRA and Testicular Cancer
CTAG1B Xq28 CTAG, ESO1, CT6.1, CTAG1, LAGE-2, LAGE2B, NY-ESO-1 -CTAG1B and Testicular Cancer
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Testicular Cancer
PDE11A 2q31.2 PPNAD2 -PDE11A and Testicular Cancer
TGCT1 Xq27 -TGCT1 and Testicular Cancer
FOXL2 3q22.3 BPES, PFRK, POF3, BPES1, PINTO -FOXL2 and Testicular Cancer
PTER 10p13 HPHRP, RPR-1 -PTER and Testicular Cancer
MAGEA4 Xq28 CT1.4, MAGE4, MAGE4A, MAGE4B, MAGE-41, MAGE-X2 -MAGEA4 and Testicular Cancer
CLU 8p21.1 CLI, AAG4, APOJ, CLU1, CLU2, KUB1, SGP2, APO-J, SGP-2, SP-40, TRPM2, TRPM-2, NA1/NA2 -Clusterin and Testicular Cancer
HLA-DRB1 6p21.32 SS1, DRB1, HLA-DRB, HLA-DR1B -HLA-DRB1 and Testicular Cancer
MYD88 3p22.2 MYD88D -MYD88 and Testicular Cancer
TERC 3q26.2 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Testicular Cancer
NR5A1 9q33.3 ELP, SF1, FTZ1, POF7, SF-1, AD4BP, FTZF1, SPGF8, SRXY3, hSF-1 -NR5A1 and Testicular Cancer
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Testicular Cancer
MAGEA3 Xq28 HIP8, HYPD, CT1.3, MAGE3, MAGEA6 -MAGEA3 and Testicular Cancer
MIB1 18q11.2 MIB, DIP1, ZZZ6, DIP-1, LVNC7, ZZANK2 -MIB1 and Testicular Cancer
GPER1 7p22.3 mER, CEPR, GPER, DRY12, FEG-1, GPR30, LERGU, LyGPR, CMKRL2, LERGU2, GPCR-Br -GPER and Testicular Cancer
CTCF 16q22.1 MRD21 -CTCF and Testicular Cancer
BCL10 1p22.3 CLAP, mE10, CIPER, IMD37, c-E10, CARMEN -BCL10 and Testicular Cancer
SNRPN 15q11.2 SMN, PWCR, SM-D, sm-N, RT-LI, HCERN3, SNRNP-N, SNURF-SNRPN -SNRPN and Testicular Cancer
CDKN2D 19p13.2 p19, INK4D, p19-INK4D -CDKN2D and Testicular Cancer
SOX17 8q11.23 VUR3 -SOX17 and Testicular Cancer
CD79A 19q13.2 IGA, MB-1 -CD79A and Testicular Cancer
SLC5A5 19p13.11 NIS, TDH1 -SLC5A5 and Testicular Cancer
MCC 5q22.2 MCC1 -MCC and Testicular Cancer
GSTT1 22q11.23 -GSTT1 and Testicular Cancer
DCC 18q21.2 CRC18, CRCR1, MRMV1, IGDCC1, NTN1R1 -DCC and Testicular Cancer
CTCFL 20q13.31 CT27, BORIS, CTCF-T, HMGB1L1, dJ579F20.2 -CTCFL and Testicular Cancer
CKAP4 12q23.3 p63, CLIMP-63, ERGIC-63 -CKAP4 and Testicular Cancer
HLA-B 6p21.33 AS, HLAB, B-4901 -HLA-B and Testicular Cancer
SCGB3A1 5q35.3 HIN1, HIN-1, LU105, UGRP2, PnSP-2 -SCGB3A1 and Testicular Cancer
CYP3A4 7q22.1 HLP, CP33, CP34, CYP3A, NF-25, CYP3A3, P450C3, CYPIIIA3, CYPIIIA4, P450PCN1 -CYP3A4 and Testicular Cancer
ETV6 12p13.2 TEL, THC5, TEL/ABL -ETV6 and Testicular Cancer
HLA-DQB1 6p21.32 IDDM1, CELIAC1, HLA-DQB -HLA-DQB1 and Testicular Cancer
MAGEB2 Xp21.2 DAM6, CT3.2, MAGE-XP-2 -MAGEB2 and Testicular Cancer
MC2R 18p11.21 ACTHR -MC2R and Testicular Cancer
PATZ1 22q12.2 ZSG, MAZR, PATZ, RIAZ, ZBTB19, ZNF278, dJ400N23 -PATZ1 and Testicular Cancer
CYP1A2 15q24.1 CP12, P3-450, P450(PA) -CYP1A2 and Testicular Cancer
CYP1B1 2p22.2 CP1B, GLC3A, CYPIB1, P4501B1 -CYP1B1 and Testicular Cancer
CYP3A5 7q22.1 CP35, PCN3, CYPIIIA5, P450PCN3 -CYP3A5 and Testicular Cancer
APAF1 12q23.1 CED4, APAF-1 -APAF1 and Testicular Cancer
IMP3 15q24.2 BRMS2, MRPS4, C15orf12 -IMP3 and Testicular Cancer
FSHR 2p21-p16 LGR1, ODG1, FSHRO -FSHR and Testicular Cancer
SNX29 16p13.13-p13.12 RUNDC2A, A-388D4.1 -SNX29 and Testicular Cancer
CDH2 18q12.1 CDHN, NCAD, CD325, CDw325 -CDH2 and Testicular Cancer
CD79B 17q23.3 B29, IGB, AGM6 -CD79B and Testicular Cancer
CLP1 11q12.1 HEAB, hClp1 -CLP1 and Testicular Cancer
MCF2 Xq27.1 DBL, ARHGEF21 -MCF2 and Testicular Cancer
CTGF 6q23.2 CCN2, NOV2, HCS24, IGFBP8 -CTGF and Testicular Cancer
PITX1 5q31.1 BFT, CCF, POTX, PTX1, LBNBG -PITX1 and Testicular Cancer
KNL1 15q15.1 D40, CT29, Spc7, CASC5, MCPH4, hKNL-1, AF15Q14, PPP1R55, hSpc105 -CASC5 and Testicular Cancer
SOX1 13q34 -SOX1 and Testicular Cancer
FAS 10q23.31 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Testicular Cancer
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Testicular Cancer
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Testicular Cancer
PPP1R13L 19q13.32 RAI, RAI4, IASPP, NKIP1 -PPP1R13L and Testicular Cancer
HSD3B2 1p12 HSDB, HSD3B, SDR11E2 -HSD3B2 and Testicular Cancer
PTPRC 1q31.3-q32.1 LCA, LY5, B220, CD45, L-CA, T200, CD45R, GP180 -PTPRC and Testicular Cancer
SLC43A1 11q12.1 LAT3, PB39, POV1, R00504 -SLC43A1 and Testicular Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Tourne M, Radulescu C, Allory Y
[Testicular germ cell tumors: Histopathological and molecular features].
Bull Cancer. 2019; 106(4):328-341 [PubMed] Related Publications
In 2016, the WHO classification of testicular germ cell tumors was revised considering advances in the understanding of their tumorigenesis and molecular features. This restructuring led to a division into two major groups with, on one hand, prepubertal-type tumors, not derived from germ cell neoplasia in situ (GCNIS), and on the other hand, postpubertal-type tumors, GCNIS-derived, which occur in youg men (seminoma and non seminomatous germ cell tumors - embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma essentially). The term germ cell neoplasia in situ is consensually accepted as a new terminology for the precursor lesion. In this new classification, the term "spermatocytic seminoma" is replaced by "spermatocytic tumor", reclassified among non-GCNIS-derived tumors. The purpose of this change of nomenclature is to reflect the usually non-aggressive behaviour of this tumor and to avoid any confusion with usual seminoma. The spectrum of trophoblastic tumors continues to expand with the description of new rare entities such as the cystic trophoblastic tumor, the placental site trophoblastic tumor and the epithelioid trophoblastic tumor. This review aims to provide a focus on testicular germ cell tumors highlighting the new immunohistochemical and molecular features responsible for the restructuring of classification. The TNM staging is presented according to the AJCC 8th edition 2017 update.

Qin J, Cui N, Hou R, et al.
Association between androgen receptor gene polymorphisms and testicular germ cell tumor: A systematic review and meta-analysis.
J Cancer Res Ther. 2019; 15(Supplement):S60-S68 [PubMed] Related Publications
Objective: To estimate association between androgen receptor (AR) gene polymorphisms and testicular germ cell tumor (TGCT) susceptibility.
Materials and Methods: Systematic search of studies on the association between AR gene polymorphisms and TGCT susceptibility was conducted. Odds ratios and 95% confidence intervals were used to pool effect size.
Results: For CAG repeat, no evidence was found for association between (>25 vs. ≤25), (>25 vs. 21-25), (<21 vs. 21-25), (others vs. 21-25), (>23 vs. ≤23), (<21 vs. ≥21), (<21 vs. ≥21)'s some subgroups and TGCT susceptibility, which showed stability. In (>24 vs. ≤24), (>24 vs. 21-24), (<21 vs. 21-24), and (others vs. 21-24) and almost all of their subgroups, increased TGCT risk was found without sensitivity analysis. For GGN, no statistical change of TGCT risk was found in (<23 vs. ≥23), (<23 vs. 23), which showed stability. For single nucleotide polymorphism (SNP) rs6152 G > A, rs1204038 G > A and rs2361634 A > G, no statistical change was found without sensitivity analysis.
Conclusions: GGN repeat number <23 may not be associated with TGCTs susceptibility. However, there was insufficient data to fully confirm association in GGN repeat number >23, CAG repeat number, SNP rs6152, rs1204038, and rs2361634.

Miyai K, Ito K, Nakanishi K, Tsuda H
Cell-to-cell variation of chromosomal number in the adult testicular germ cell tumors: a comparison of chromosomal instability among histological components and its putative role in tumor progression.
Virchows Arch. 2019; 474(6):711-720 [PubMed] Related Publications
By allelotyping analysis, we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma, then to embryonal carcinoma in mixed-type testicular germ cell tumors (TGCTs), and detected that loss of heterozygosity events in seminoma components in mixed tumors were more frequent than those in pure seminomas. To elucidate a role of chromosomal instability in the progression of non-seminomatous germ cell tumor (NSGCT), we performed fluorescence in situ hybridization with centromeric probes for chromosomes 1, 7, 8, 12, 17, and X on a cohort of 52 TGCT cases with 103 histologically distinct components: 39 GCNIS lesions (16 and 23 in tumors with and without NSGCT components, respectively), 39 seminomas (27 as pure seminomas and 12 in mixed tumors), and 25 embryonal carcinomas. On a total component basis, both the mean copy number per tumor cell nucleus and the deviations from the modal number of all chromosomes examined significantly increased from GCNIS to seminoma, then to embryonal carcinoma with few exceptions. Seminoma components in mixed tumors showed a significantly greater extent of chromosomal instability in chromosomes 8 and 12 than pure seminomas, whereas no statistically significant difference was observed between GCNIS lesions with and without NSGCT components. These results suggest that not only aneuploidy, but also the cell-to-cell variation of chromosomal number is a sensitive indicator of chromosomal instability and would be implicated in the progression of NSGCT.

Batool A, Liu XM, Zhang CL, et al.
Recent advances in the regulation of testicular germ cell tumors by microRNAs.
Front Biosci (Landmark Ed). 2019; 24:765-776 [PubMed] Related Publications
Testicular germ cell tumors (TGCTs) are generally rare but represent the most common solid tumors in young men. They are classified broadly into seminoma, which resemble primordial germ cells (PGCs), and non-seminoma, which are either undifferentiated (embryonic carcinoma) or differentiated (teratoma, yolk sac tumor, choriocarcinomas) patterning. A widespread role for microRNAs (miRNAs), in diverse molecular processes driving initiation and progression of various types of TGCTs has been recently studied. We discuss the involvement of different miRNAs in the development and progression of different types of TGCTs. Moreover, we highlight the aberrant expression of miRNAs in TGCTs and several targets, which may define miRNAs as oncomiRs or tumor suppressors. A better understanding of miRNA biology may ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies against TGCTs.

Batool A, Karimi N, Wu XN, et al.
Testicular germ cell tumor: a comprehensive review.
Cell Mol Life Sci. 2019; 76(9):1713-1727 [PubMed] Related Publications
Testicular tumors are the most common tumors in adolescent and young men and germ cell tumors (TGCTs) account for most of all testicular cancers. Increasing incidence of TGCTs among males provides strong motivation to understand its biological and genetic basis. Gains of chromosome arm 12p and aneuploidy are nearly universal in TGCTs, but TGCTs have low point mutation rate. It is thought that TGCTs develop from premalignant intratubular germ cell neoplasia that is believed to arise from the failure of normal maturation of gonocytes during fetal or postnatal development. Progression toward invasive TGCTs (seminoma and nonseminoma) then occurs after puberty. Both inherited genetic factors and environmental risk factors emerge as important contributors to TGCT susceptibility. Genome-wide association studies have so far identified more than 30 risk loci for TGCTs, suggesting that a polygenic model fits better with the genetic landscape of the disease. Despite high cure rates because of its particular sensitivity to platinum-based chemotherapy, exploration of mechanisms underlying the occurrence, progression, metastasis, recurrence, chemotherapeutic resistance, early diagnosis and optional clinical therapeutics without long-term side effects are urgently needed to reduce the cancer burden in this underserved age group. Herein, we present an up-to-date review on clinical challenges, origin and progression, risk factors, TGCT mouse models, serum diagnostic markers, resistance mechanisms, miRNA regulation, and database resources of TGCTs. We appeal that more attention should be paid to the basic research and clinical diagnosis and treatment of TGCTs.

Leonetti E, Gesualdi L, Scheri KC, et al.
c-Src Recruitment is Involved in c-MET-Mediated Malignant Behaviour of NT2D1 Non-Seminoma Cells.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications

Oing C, Verem I, Mansour WY, et al.
5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells.
Int J Mol Sci. 2018; 20(1) [PubMed] Free Access to Full Article Related Publications
Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.

Bruno C, Blagoskonov O, Barberet J, et al.
Sperm imprinting integrity in seminoma patients?
Clin Epigenetics. 2018; 10(1):125 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular germ cell tumor such as seminoma is strongly associated with male reproductive problems commonly associated with the alteration of sperm parameters as described in testicular dysgenesis syndrome. Interestingly, numerous studies have reported that the precursor of germ cell cancer, germ cell neoplasia in situ (GCNIS), present similarities to fetal gonocytes, specifically characterized by global DNA hypomethylation particularly on imprinting sequences. These disorders may have a common origin derived from perturbations of embryonal programming during fetal development. Presently, there is no available information concerning the sperm DNA methylation patterns of testicular cancer patients. For the first time, we evaluated the sperm imprinting of seminoma patients. A total of 92 cryopreserved sperm samples were included, 31 before seminoma treatment (S): 23 normozoospermic (SN) and 8 oligozoospermic (SO) and 61 sperm controls samples: 31 normozoospermic (N) and 30 oligozoospermic (O). DNA methylation levels of seven differentially methylated regions (DMRs) of imprinted genes [H19/IGF2: IG-DMR (CTCF3 and CTCF6 of H19 gene); IGF2-DMRs (DMR0 and DMR2); MEG3/DLK1:IG-DMR; SNURF:TSS-DMR; KCNQ1OT1:TSS-DMR] were assessed by pyrosequencing. All comparative analyses were adjusted for age.
RESULTS: Comparisons of sperm DNA methylation levels between seminoma (S) and normozoospermic (N) samples showed a significant difference for the SNURF sequence (p = 0.017), but after taking into account the sperm parameters, no difference was observed. However, we confirmed a significant association between oligozoospermia (O) and imprinting defects for H19/IGF2-CTCF6 (p = 0.001), MEG3/DLK1 (p = 0.017), IGF2-DMR2 (p = 0.022), and SNURF (p = 0.032) in comparison with control groups (N).
CONCLUSIONS: This study highlights the high risk of sperm imprinting defects in cases of oligozoospermia and shows for the first time that seminoma patients with normal spermatogenesis present sperm imprinting integrity. These data suggest a low probability of the involvement of a common imprinting defect in fetal cells leading to both TGCT and subfertility.

Shimizu N, Matsuda M
Identification of a Novel Zebrafish Mutant Line that Develops Testicular Germ Cell Tumors.
Zebrafish. 2019; 16(1):15-28 [PubMed] Related Publications
Testicular tumors are the most common solid malignant tumors in men 20-35 years of age. Although most of testicular tumors are curable, current treatments still fail in 15%-20% of patients. However, insufficient understanding of the molecular basis and lack of animal models limit development of more effective treatments. This study reports the identification of a novel zebrafish mutant line, ns1402, which develops testicular germ cell tumors (TGCTs). While both male and female ns1402 mutants were fertile at young age, male ns1402 mutants became infertile as early as 9 months of age. This infertility was associated with progressive loss of mature sperm. Failure of spermatogenesis was, at least in part, explained by progressive loss of mature Leydig cells, a source of testosterone that is essential for spermatogenesis. Interestingly, TGCTs in ns1402 mutants contained a large number of Sertoli cells and gene expression profiles of Sertoli cells were altered before loss of mature Leydig cells. This suggests that changes in Sertoli cell properties happened first, followed by loss of mature Leydig cells and failure of spermatogenesis. Taken together, this study emphasizes the importance of cell-cell interactions and cell signaling in the testis for spermatogenesis and tissue homeostasis.

Williams LA, Mills L, Hooten AJ, et al.
Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children's Oncology Group.
Br J Cancer. 2018; 119(7):864-872 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Abnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology.
METHODS: Using the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours [YST], 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values.
RESULTS: We identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST.
CONCLUSIONS: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

Kaushik A, Bhartiya D
Pluripotent Very Small Embryonic-Like Stem Cells in Adult Testes - An Alternate Premise to Explain Testicular Germ Cell Tumors.
Stem Cell Rev Rep. 2018; 14(6):793-800 [PubMed] Related Publications
Developmental exposure to endocrine disruptors has resulted in the increased incidence of infertility and testicular germ cell tumors (T2GCT) in young men residing in developed countries. Unlike T1GCT (infants and young children) and T3GCT (aged men), T2GCT arise from CIS/GCNIS that develops from pre-CIS. Pre-CIS represents undifferentiated, growth-arrested gonocytes that persist in fetal testes due to endocrine disruption. However, whether pre-CIS truly exist, do CIS develop into T2GCT, why no CIS in T1GCT/T3GCT, why germ cell tumors (GCT) also occur along midline at extra-gonadal sites, why T1GCT show partial erasure and T2GCT show complete erasure of genomic imprints are open questions that are awaiting answers. We propose that rather than pre-CIS, pluripotent, very small embryonic-like stem cells (VSELs) get affected by exposure to endocrine disruption. Since VSELs are developmentally equivalent to primordial germ cells (PGCs), T2GCT cells show complete erasure of genomic imprints and CIS represents growth-arrested clonally expanding stem/progenitor cells. PGCs/VSELs migrate along the midline to various organs and this explains why GCT occur along the midline, T1GCT show partial erasure of imprints as they develop from migrating PGCs. T3GCT possibly reflects effects of aging due to compromised differentiation and expansion of pre-meiotic spermatocytes. Absent spermatogenesis in pre-pubertal and aged testes explains absence of CIS in T1GCT and T3GCT. Endocrine disruptors possibly alter epigenetic state of VSELs and thus rather than maintaining normal tissue homeostasis, VSELs undergo increased proliferation and compromised differentiation resulting in reduced sperm count, infertility and TGCT. This newly emerging understanding offers alternate premise to explain TGCT and warrants further exploration.

Niu Y, Fuerhaiti S, Bi X, et al.
[Correlation of 41 loci of single nucleotide polymorphisms with testicular germ cell tumor].
Zhonghua Nan Ke Xue. 2018; 24(7):602-607 [PubMed] Related Publications
Objective: To identify genetic susceptibility genes and the loci of their single nucleotide polymorphisms (SNPs) in patients with testicular germ cell tumor (TGCT) and provide some new ideas for the prediction, diagnosis and treatment of TGCT.
METHODS: We identified 41 SNP loci of TGCT-related genetic susceptibility genes from the literature published abroad. Using the iMLDRTM genotyping technique, we examined the SNP loci of the genetic susceptibility genes in the blood samples from 76 TGCT patients (aged 16-68 years) and 148 healthy men (aged 22-61 years) in China and analyzed their correlation with TGCT.
RESULTS: In China, TGCT was found to be correlated with the SNP loci rs2978381, rs10146204, rs12435857 and rs1256063 of the ESR2 gene, rs9397080 of the ESR1 gene, rs11202586 of the PTEN gene, rs2606345 and rs4646903 of the CYP1A1 gene, and rs1456432 of the CYP19A1 gene.
CONCLUSIONS: The results of our study indicated some difference in the positive SNP loci of the TGCT patients between Chinese and foreign cohorts as well as in different groups in China.

Zhang X, Shen D, Wang Y
Detection of the DICER1 hotspot mutation alongside immunohistochemical analysis may provide a better diagnostic measure for ovarian Sertoli-Leydig cell tumors.
Pathol Res Pract. 2018; 214(9):1370-1375 [PubMed] Related Publications
BACKGROUND: To evaluate the clinicopathological and histopathological characteristics of ovarian Sertoli-Leydig cell tumors (SLCTs) in relation to differential diagnosis, and patient prognosis.
METHODS: A review of clinical data, pathological morphology and immunohistochemical analysis of SLCTs were performed in 18 SLCTs patients. The DICER1 gene mutation was assessed in eight cases that were obtained from in-house surgical resections.
RESULTS: Among 18 SLCTs patients, three cases had well-differentiated tumors, 8 cases had moderately-differentiated tumors, and the remaining 7 cases had poorly-differentiated tumors. Among the moderately-differentiated tumors, three cases occurred coincidently with other diseases - one case occurred with endometrial carcinoma (grade I), and two cases with endometrial carcinoma of the ovary (grade 2 and grade 3). Immunohistochemical staining for α-inhibin, calretinin, and FOXL2 was positive in all the biopsies tested. The intensity of staining varied depending on the percentage of Sertoli cells and the primitive gonad interstitial composition. DICER1 mutations were detected in three of eight cases that were evaluated and were significantly more in low age range patients (P < 0.05). The initial symptoms of these three cases were sexual changes and elevation of androgen levels. The follow-up time in this study ranged from 3 to 87 months with the mean follow-up time of 29.1 months. Prognosis was generally favorable. There was no recurrence or metastasis in any patient, except for one case with recurrence of endometrial carcinoma.
CONCLUSION: The clinical presentation of SLCTs can be both varied and complex. Pathological examination is imperative for both diagnostic and prognostic grading. Immunohistochemical stain of α-inhibin, FOXL2, and calretinin and genetic testing for DICER1 mutations will be more potent for differential diagnosis.

Eldar-Geva T, Gross-Tsur V, Hirsch HJ, et al.
Incomplete methylation of a germ cell tumor (Seminoma) in a Prader-Willi male.
Mol Genet Genomic Med. 2018; 6(5):811-818 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by lack of satiety leading to morbid obesity, variable degrees of mental retardation, behavior disorders, short stature, and hypogonadism. The underlying genetic cause for PWS is an imprinting defect resulting from a lack of expression of several paternally inherited genes embedded within the 15q11.2-q13 region. Although the clinical expression of hypogonadism in PWS is variable, there are no known cases of fertility in PWS men. In this paper, we described a pure, nearly diploid seminoma in an apparently 32 year-old infertile man with PWS due to maternal uniparental disomy (UPD) on chromosome 15. The development of a germ cell tumor in this subject was an unanticipated result. The aim of this study was to explore the origin of the germ cell tumor in this PWS male patient.
METHODS: To explain the origin of the germ cell tumor (seminoma) in our PWS patient we have characterized the tumor for cell morphology and tumor type by pathological examination (H&E and immuno-stainings), evaluated its karyotype by chromosomal microarray analysis and confirmed its UPD origin by haplotype analysis. In addition, DNA methylation status of the PWS- and H19- imprinting centers in wild-type and affected fibroblasts, patient derived induced pluripotent stem cells (iPSCs), and PWS seminoma were determined by bisulfite DNA colony sequencing.
RESULTS: To explain the apparent contradiction between the existence of a germ cell tumor and hypogonadism we first confirmed the germ cell origin of the tumor. Next, we determined the tumor chromosomal composition, and validated the presence of a maternal UPD in all examined cell types from this patient. Finally, we characterized the maternal imprints in the PWS and H19 imprinting centers in the tumor and compared them with patient's fibroblasts and iPSCs derived from them. Unpredictably, methylation was reduced to 50% in the tumor, while preserved in the other cell types.
CONCLUSION: We infer from this assay that the loss of methylation in the PWS-IC specifically in the tumor of our patient is most likely a locus-specific event resulting from imprint relaxation rather than from general resetting of the imprints throughout the genome during germ line specification.

Zhao M, Zhao DH, He HY, et al.
[Clinicopathologic and molecular characterizations of Sertoli cell tumor, not otherwise specified of the testis].
Zhonghua Bing Li Xue Za Zhi. 2018; 47(7):505-510 [PubMed] Related Publications

Loveday C, Law P, Litchfield K, et al.
Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.
Eur Urol. 2018; 74(3):248-252 [PubMed] Related Publications
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene.
PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.

Shi Z, Chen J, Zhang X, et al.
Ataxin-3 promotes testicular cancer cell proliferation by inhibiting anti-oncogene PTEN.
Biochem Biophys Res Commun. 2018; 503(1):391-396 [PubMed] Related Publications
Human Ataxin-3 protein was first identified as a transcript from patients with Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3). Recent studies have demonstrated that Ataxin-3 is involved in gastric cancer and lung cancer. However, the role of Ataxin-3 in testicular cancer (TC) remains poorly understood. This study aims to explore the significance of Ataxin-3 expression in TC. Firstly, we investigated 53 paired TC and para-tumor tissues and found that Ataxin-3 was overexpressed in TC tissues, and this overexpression of Ataxin-3 was correlated with tumor stages. Functionally, Ataxin-3 overexpression promoted cell proliferation, and Ataxin-3 knockdown inhibited cell proliferation. In addition, up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT/mTOR pathway. Conversely, inhibition of Ataxin-3 suppressed the expression of p-AKT and p-mTOR, and increased the expression of p-4EBP1. These findings may provide a better understanding about the mechanism of TC and suggest that Ataxin-3 may be a potential prognostic biomarker and therapeutic target for TC.

Paumard-Hernández B, Calvete O, Inglada Pérez L, et al.
Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.
Int J Cancer. 2018; 143(8):1954-1962 [PubMed] Related Publications
Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10

Lewin J, Soltan Ghoraie L, Bedard PL, et al.
Gene expression signatures prognostic for relapse in stage I testicular germ cell tumours.
BJU Int. 2018; 122(5):814-822 [PubMed] Related Publications
OBJECTIVES: To identify differentially expressed genes between relapsed and non-relapsed clinical stage I testicular germ cell tumours (TGCTs).
MATERIALS AND METHODS: We reviewed patients with clinical stage I non-seminoma and seminoma from an institutional database (2000-2012) who were managed by active surveillance. Patients with non-relapsed non-seminoma and non-relapsed seminoma were defined as being relapse-free after 2 and 3 years of surveillance, respectively. RNA extraction and gene expression analysis was performed on archival primary tumour samples and gene-set enrichment analysis (GSEA) was conducted in order to identify differentiating biological pathways.
RESULTS: A total of 57 patients (relapsed non-seminoma, n = 12; relapsed seminoma, n =15; non-relapsed non-seminoma, n = 15; non-relapsed seminoma, n = 15) were identified, with a median (range) relapse time of 5.6 (2.5-18.1) and 19.3 (4.7-65.3) months in the relapsed non-seminoma and relapsed seminoma cohorts, respectively. A total of 1 039 differentially expressed genes were identified that separated relapsed and non-relapsed groups. In patients with relapse, GSEA revealed enrichment in pathways associated with differentiation, such as skeletal development (i.e. FGFR1, BMP4, GLI2, SPARC, COL2A1), tissue (i.e. BMP4, SPARC, COL13A1) and bone remodelling (i.e. CARTPT, GLI2, MGP). A discriminative gene expression profile between relapsed and non-relapsed cases was discovered when combining non-seminoma and seminoma samples using 10- and 30-probe signatures; however, this profile was not observed in the seminoma and non-seminoma cohorts individually.
CONCLUSION: A discriminating signature for relapsed disease was identified for clinical stage I TGCT that we were not able to identify by histology alone. Further validation is required to determine if this signature provides independent prognostic information to standard pathological risk factors.

Michalova K, Michal M, Sedivcova M, et al.
Solid pseudopapillary neoplasm (SPN) of the testis: Comprehensive mutational analysis of 6 testicular and 8 pancreatic SPNs.
Ann Diagn Pathol. 2018; 35:42-47 [PubMed] Related Publications
BACKGROUND: Recently, we came with the theory of a possible relationship between a group of testicular and pancreatic tumors. We used one case of a pancreatic analogue solid pseudopapillary neoplasm of the testis composed partially of areas reminiscent of solid pseudopapillary neoplasm (SPN) of the pancreas and partially of structures identical to primary signet ring stromal tumor of the testis (PSRSTT) as a connecting link between these two entities. After demonstrating that PSRSTT and pancreatic analogue SPN of the testis share the same immunoprofile and genetic features characteristic for pancreatic SPN, we came to the conclusion that pancreatic analogue SPN of the testis and PSRSTT represent a morphological spectrum of a single entity and that both are related to the pancreatic SPN.
DESIGN: The aim of this study is to present a series of 6 cases of testicular tumors, which lacked the signet ring cell component and were thus morphologically very similar to the SPN of the pancreas. The goal of this study is to compare the genetic background of these testicular tumors that are obviously related to the PSRSTT/pancreatic analogue SPN of the testis with the series of 8 pancreatic SPN.
RESULTS: The mutational analysis revealed an oncogenic somatic mutation in the exon 3 of the CTNNB1 (β-catenin) gene in all analyzable (5/6) testicular and all pancreatic (8/8) tumors. The immunoprofile (positivity with β-catenin, CD10, vimentin, NSE, CD56, and negativity with inhibin, calretinin, chromogranin) was identical in all testicular and pancreatic tumors.
CONCLUSION: This study expanded the morphological spectrum of the PSRSTT/pancreatic analogue SPN of the testis by adding 6 cases without the signet ring cell component. Considering the obvious analogy of PSRSTT/pancreatic analogue SPN of the testis/SPN of the testis and their relationship to the pancreatic SPN we propose the collective term "solid pseudopapillary neoplasm of the testis" for these tumors. The mutational profile of the SPN of the testis and pancreas was the same in both groups of tumors which we consider as a final proof that SPN of the testis is identical to the SPN of the pancreas.

Radtke A, Hennig F, Ikogho R, et al.
The Novel Biomarker of Germ Cell Tumours, Micro-RNA-371a-3p, Has a Very Rapid Decay in Patients with Clinical Stage 1.
Urol Int. 2018; 100(4):470-475 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Accumulating evidence suggests serum levels of microRNA (miR)-371a-3p to be a novel tumour marker of testicular germ cell tumours (GCTs). Presently, there is only limited information regarding the velocity of decline of serum levels in response to treatment.
PATIENTS AND METHODS: Twenty-four patients with testicular GCT (20 seminoma, 4 nonseminoma, median age 40 years) with clinical stage 1 had measurements of serum levels of miR-371a-3p preoperatively and repeatedly on the following 3 days. Three had additional tests done within 24 h after surgery. Measurement results were analysed using descriptive statistical methods.
RESULTS: Serum levels dropped to 2.62, 1.27, and 0.47% of the preoperative level within 1, 2, and 3 days, respectively. The computed half-life amounts to 3.7-7 h. The velocity of decay is significantly associated with tumour size.
CONCLUSIONS: Serum-levels of miR-371a-3p have a short half-life of less than 12 h. The rapid decay after treatment represents a valuable feature confirming the usefulness of miR-371a-3p as a valuable serum biomarker of GCT.

Behnert A, Auber B, Steinemann D, et al.
KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition?
Am J Med Genet A. 2018; 176(6):1449-1454 [PubMed] Related Publications
KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11) being the result of either loss-of-function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand-dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left-sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow-up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future.

Vilela-Salgueiro B, Barros-Silva D, Lobo J, et al.
Germ cell tumour subtypes display differential expression of microRNA371a-3p.
Philos Trans R Soc Lond B Biol Sci. 2018; 373(1748) [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Testicular germ cell tumours (TGCTs) are a heterogeneous group of neoplasms, mostly affecting young men. Curability rates are high and adequate treatment relies on careful and accurate pathological and clinical assessment. Indeed, TGCTs' histopathological subtyping is critical for adequate therapeutic decision. Considering the limitation of currently available serum biomarkers, novel candidates have been proposed, most notably miR-371a-3p, which outperformed classical serum markers, but no detailed information concerning TGCT subtype was available. Thus, we carried out evaluation of miR-371a-3p expression levels among TGCT subtypes using a consecutive cohort of tissue samples. MiR-371a-3p discriminated TGCTs from control tissues with high sensitivity and specificity (AUC = 0.99). Furthermore, seminomas displayed higher miR-371a-3p expression levels compared to non-seminomatous TGCTs, which also showed significant differences among them. Nonetheless, prepubertal TGCTs depicted lower miR-371a-3p expression levels than postpubertal TGCTs. Globally, miR-371a-3p expression levels decreased in parallel with progressive cell differentiation. We concluded that miR-371a-3p is TGCTs-specific and it might be clinically useful for early detection and disease monitoring.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

Miyazaki T, Fukui M, Inagaki E, et al.
Identification of Two Additional Genomic Loci Responsible for experimentally induced testicular teratoma 2 and 3 (ett2 and ett3).
Zoolog Sci. 2018; 35(2):172-178 [PubMed] Related Publications
Experimental testicular teratomas (ETTs) can be induced in 129/Sv mouse by E12.5 fetal testes transplant into adult testes. Previously, we conducted linkage analysis to explore candidate genes possibly involved in ETT development using F2 intercross fetuses derived from F1[LTXBJ × 129/Sv- + /Ter (+ /+)] hybrids. By linkage analysis on Chr 18 and Chr 19, we identified the genomic locus for experimental testicular teratoma 1 (ett1) on Chr 18. In the present study, we conducted additional mapping and linkage analysis on teratoma susceptibility and genome composition on Chr 1-17. The results revealed two new candidate loci, experimental testicular teratoma 2 (ett2) and experimental testicular teratoma 3 (ett3), on Chr 3 and 7. Interestingly, the rates of ETT generation were increased in the case of ett2 and ett3 regions replaced with LTXBJ strain. To determine whether a polymorphic gene was present, we performed exome analysis of 129/Sv- + /Ter (+ /+) and LTXBJ. This revealed the presence of SNPs in all three loci, ett1 to ett3. ett1 contains polymorphic Mc4r; ett2 contains polymorphic Polr3c, Cd160, and Pdzk1; and ett3 contains polymorphic Prmt3. We found additional loci responsible for ETT formation, namely, ett2 and ett3, and identified candidate genes in these regions by exome analysis.

Wang Y, Gray DR, Robbins AK, et al.
Subphenotype meta-analysis of testicular cancer genome-wide association study data suggests a role for RBFOX family genes in cryptorchidism susceptibility.
Hum Reprod. 2018; 33(5):967-977 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
STUDY QUESTION: Can subphenotype analysis of genome-wide association study (GWAS) data from subjects with testicular germ cell tumor (TGCT) provide insight into cryptorchidism (undescended testis, UDT) susceptibility?
SUMMARY ANSWER: Suggestive intragenic GWAS signals common to UDT, TGCT case-case and TGCT case-control analyses occur in genes encoding RBFOX RNA-binding proteins (RBPs) and their neurodevelopmental targets.
WHAT IS KNOWN ALREADY: UDT is a strong risk factor for TGCT, but while genetic risk factors for TGCT are well-known, genetic susceptibility to UDT is poorly understood and appears to be more complex.
STUDY DESIGN, SIZE, DURATION: We performed a secondary subphenotype analysis of existing GWAS data from the Testicular Cancer Consortium (TECAC) and compared these results with our previously published UDT GWAS data, and with data previously acquired from studies of the fetal rat gubernaculum.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies from the National Cancer Institute (NCI), United Kingdom (UK) and University of Pennsylvania (Penn) that enrolled white subjects were the source of the TGCT GWAS data. We completed UDT subphenotype case-case (TGCT/UDT vs TGCT/non-UDT) and case-control (TGCT/UDT vs control), collectively referred to as 'TECAC' analyses, followed by a meta-analysis comprising 129 TGCT/UDT cases, 1771 TGCT/non-UDT cases, and 3967 unaffected controls. We reanalyzed our UDT GWAS results comprising 844 cases and 2718 controls by mapping suggestive UDT and TECAC signals (defined as P < 0.001) to genes using Ingenuity Pathway Analysis (IPA®). We compared associated pathways and enriched gene categories common to all analyses after Benjamini-Hochberg multiple testing correction, and analyzed transcript levels and protein expression using qRT-PCR and rat fetal gubernaculum confocal imaging, respectively.
MAIN RESULTS AND THE ROLE OF CHANCE: We found suggestive signals within 19 genes common to all three analyses, including RBFOX1 and RBFOX3, neurodevelopmental paralogs that encode RBPs targeting (U)GCATG-containing transcripts. Ten of the 19 genes participate in neurodevelopment and/or contribute to risk of neurodevelopmental disorders. Experimentally predicted RBFOX gene targets were strongly overrepresented among suggestive intragenic signals for the UDT (117 of 628 (19%), P = 3.5 × 10-24), TECAC case-case (129 of 711 (18%), P = 2.5 × 10-27) and TECAC case-control (117 of 679 (17%), P = 2 × 10-21) analyses, and a majority of the genes common to all three analyses (12 of 19 (63%), P = 3 × 10-9) are predicted RBFOX targets. Rbfox1, Rbfox2 and their encoded proteins are expressed in the rat fetal gubernaculum. Predicted RBFOX targets are also enriched among transcripts differentially regulated in the fetal gubernaculum during normal development (P = 3 × 10-31), in response to in vitro hormonal stimulation (P = 5 × 10-45) and in the cryptorchid LE/orl rat (P = 2 × 10-42).
LARGE SCALE DATA: GWAS data included in this study are available in the database of Genotypes and Phenotypes (dbGaP accession numbers phs000986.v1.p1 and phs001349.v1p1).
LIMITATIONS, REASONS FOR CAUTION: These GWAS data did not reach genome-wide significance for any individual analysis. UDT appears to have a complex etiology that also includes environmental factors, and such complexity may require much larger sample sizes than are currently available. The current methodology may also introduce bias that favors false discovery of larger genes.
WIDER IMPLICATIONS OF THE FINDINGS: Common suggestive intragenic GWAS signals suggest that RBFOX paralogs and other neurodevelopmental genes are potential UDT risk candidates, and potential TGCT susceptibility modifiers. Enrichment of predicted RBFOX targets among differentially expressed transcripts in the fetal gubernaculum additionally suggests a role for this RBP family in regulation of testicular descent. As RBFOX proteins regulate alternative splicing of Calca to generate calcitonin gene-related peptide, a protein linked to development and function of the gubernaculum, additional studies that address the role of these proteins in UDT are warranted.
STUDY FUNDING/COMPETING INTEREST(S): The Eunice Kennedy Shriver National Institute for Child Health and Human Development (R01HD060769); National Center for Research Resources (P20RR20173), National Institute of General Medical Sciences (P20GM103464), Nemours Biomedical Research, the Testicular Cancer Consortium (U01CA164947), the Intramural Research Program of the NCI, a support services contract HHSN26120130003C with IMS, Inc., the Abramson Cancer Center at Penn, National Cancer Institute (CA114478), the Institute of Cancer Research, UK and the Wellcome Trust Case-Control Consortium (WTCCC) 2. None of the authors reports a conflict of interest.

Verrier F, Dubois d'Enghien C, Gauthier-Villars M, et al.
Mutiple DICER1-related lesions associated with a germline deep intronic mutation.
Pediatr Blood Cancer. 2018; 65(6):e27005 [PubMed] Related Publications
Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli-Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.

Litchfield K, Loveday C, Levy M, et al.
Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene.
Eur Urol. 2018; 73(6):828-831 [PubMed] Related Publications
Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation.
PATIENT SUMMARY: In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors.

Das MK, Furu K, Evensen HF, et al.
Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours.
Sci Rep. 2018; 8(1):2462 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Testicular germ cell tumour (TGCT) is the most common cancer in young men in large parts of the world, but the aetiology is mainly unknown. Genome-wide association studies have so far identified about 50 susceptibility loci associated with TGCT, including SPRY4. SPRY4 has shown tumour suppressor activity in several cancer cells, such as lung and prostate, while it was found to act as an oncogene in ovarian cancer. An intronic region within the SPRY4 gene produces a long non-coding RNA, SPRY4-IT1, which has been reported to act as an oncogene in melanoma, breast cancer, and colorectal cancer, and as a tumour suppressor in lung cancer. The roles of SPRY4 and SPRY4-IT1 in TGCT development are yet unknown. We found higher expression levels of SPRY4, both mRNA and protein, and of SPRY4-IT1 in human TGCT than in normal adult testis. Small-interfering RNA (siRNA)-mediated transient knockdown of SPRY4 and SPRY4-IT1 in two TGCT cell lines 833 K and NT2-D1 resulted in decreased cell growth, migration, and invasion. Knockdown of SPRY4 and SPRY4-IT1 also led to a significant reduction in the phosphorylation of Akt. Our findings indicate that SPRY4 and SPRY4-IT1 may act as oncogenes in TGCTs via activation of the PI3K / Akt signalling pathway.

Agaimy A, Moskalev EA, Weisser W, et al.
Low-grade Endometrioid Stromal Sarcoma of the Paratestis: A Novel Report With Molecular Confirmation of JAZF1/SUZ12 Translocation.
Am J Surg Pathol. 2018; 42(5):695-700 [PubMed] Related Publications
Tumors with Müllerian-like serous or mucinous phenotypes originating in the testis and its adnexa are rare neoplasms that have been increasingly recognized in recent years. Cystadenomas with or without ovarian-type stroma, borderline tumors, and adenocarcinomas are the main documented types. Although a handful cases of putative endometrioid adenocarcinomas have been reported, to our knowledge no case of endometrial stromal-type neoplasm has ever been reported in the literature. A 59-year-old man presented with a 2 cm left intrascrotal mass that was found on sonographic examination to arise from the epididymal tail with prominent vascularization. He was otherwise healthy without significant clinical history, endocrinopathy, or external hormone therapy. His testicular tumor markers (beta-HCG, AFP) were normal. Histologic examination of the resection showed a multinodular tumor closely associated with the epididymis and composed of monotonous rounded to ovoid cells with scanty cytoplasm and prominent spiral-like arterioles and capillaries. Mitotic activity was high. No other tumor component was seen. Immunohistochemistry revealed strong and diffuse expression of vimentin, CD10, estrogen receptor, and progesterone receptor. Molecular examination (performed on paraffin-embedded tumor tissue using a 517 gene fusion next-generation sequencing assay) showed a JAZF1/SUZ12 translocation, which was then confirmed by fluorescence in situ hybridization (FISH). These findings are consistent with a low-grade endometrioid stromal sarcoma originating in the paratestis. This report represents a novel addition to the growing spectrum of Müllerian-analog testicular adnexal neoplasms.

Zhang S, Zhang Q, Sun Q, et al.
Genome Evolution Analysis of Recurrent Testicular Malignant Mesothelioma by Whole-Genome Sequencing.
Cell Physiol Biochem. 2018; 45(1):163-174 [PubMed] Related Publications
BACKGROUND/AIMS: Malignant mesothelioma of the tunica vaginalis testis is a rare and lethal disease. The genomic characteristics and genetic changes of tumor cells during the progression of this disease are unknown.
METHODS: we performed whole-genome sequencing of four successive tumor samples derived from surgery and a blood sample in a single patient.
RESULTS: All tumors were found to have significant C-to-T and T-to-C mutations, and amplification of copy number in chromosomes 1 and 12 were notified in all tumor samples. Subclone analysis revealed a parallel evolution of the tumor in this patient. We also identified some mutations in mesothelioma-associated genes such as KIF25, AHNAK, and PRDM2.
CONCLUSIONS: The results showed a comprehensive genomic change in malignant mesothelioma of the tunica vaginalis testis and provide a better understanding of the clonal evolution during tumor recurrence and metastasis.

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
Isochromosome 12p in Testicular CancerIsochromosome

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Isochromosome 12p in Testicular Cancer

Looijenga LH, Zafarana G, Grygalewicz B, et al.
Role of gain of 12p in germ cell tumour development.
APMIS. 2003; 111(1):161-71; discussion 172-3 [PubMed] Related Publications
Within the human testis, three entities of germ cell tumours are distinguished: the teratomas and yolk sac tumors of newborn and infants, the seminomas and nonseminomas of adolescents and young adults, referred to as testicular germ cell tumours (TGCT), and the spermatocytic seminomas. Characteristic chromosomal anomalies have been reported for each group, supporting their distinct pathogenesis. TGCT are the most common cancer in young adult men. The initiating pathogenetic event of these tumours occurs during embryonal development, affecting a primordial germ cell or gonocyte. Despite this intra-uterine initiation, the tumour will only be clinically manifest after puberty, with carcinoma in situ (IS) as the precursor. All invasive TGCT, both seminomas and nonseminomas, as well as CIS cells are aneuploid. The only consistent (structural) chromosomal abnormalities in invasive TGCT are gains of the short arm of chromosome 12, mostly due to isochromosome (i(12p)) formation. This suggests that an increase in copy number of a gene(s) on 12p is associated with the development of a clinically manifest TGCT. Despite the numerous (positional) candidate gene approaches that have been undertaken thus far, identification of a causative gene(s) has been hampered by the fact that most 12p gains involve rather large genomic intervals, containing unmanageable numbers of candidate genes. Several years ago, we initiated a search for 12p candidate genes using TGCT with a restricted 12p-amplification, cytogenetically identified as 12p11.2-p12.1. This approach is mainly based on identification of candidate genes mapped within the shortest region of overlap of amplification (SROA). In this review, data will be presented, which support the model that gain of 12p-sequences is associated with suppression of apoptosis and Sertoli cell-independence of CIS cells. So far, DAD-R is one of the most likely candidate genes involved in this process, possibly via N-glycosylation. Preliminary results on high through-put DNA- and cDNA array analyses of 12p-sequences will be presented.

Mostert MC, Verkerk AJ, van de Pol M, et al.
Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults.
Oncogene. 1998; 16(20):2617-27 [PubMed] Related Publications
Cytogenetically, testicular germ cell tumors of adolescents and adults (TGCTs) are characterized by gain of 12p-sequences, most often through isochromosome formation (i(12p)). Fluorescence in situ hybridization (FISH) has shown that i(12p))-negative TGCTs also cryptically contain extra 12p-sequences. The consistency of 12p-over-representation in all histological subtypes of TGCTs, including their preinvasive stage, suggests that gain of one or more genes on 12p is crucial in the development of this cancer. So far, studies aimed at the identification of the relevant gene(s) were based on the 'candidate-gene approach'. No convincing evidence in favor of or against a particular gene has been reported. We combined conventional karyotyping, comparative genomic hybridization, and FISH to identify TGCTs with amplifications of restricted regions of 12p. Out of 49 primary TGCTs (23 without i(12p), 13 with and 13 unknown), eight tumors (six without i(12p) and two unknown) showed amplifications corresponding to 12p11.1-p12.1. Using bicolour-FISH, physical mapping, and semi-quantitative polymerase chain reactions, the size of the shortest region of overlap of amplification (SROA) was estimated to be between 1750-3000 kb. In addition, we mapped a number of genes in and around this region. While fourteen known genes could be excluded as candidates based on their location outside this region, we demonstrate that KRAS2, JAW1 and SOX5 genes are localized within the SROA. While KRAS2 and JAW1 map to the proximal border of the SROA, SOX5 maps centrally in the SROA. KRAS2 and JAW1 are expressed in all TGCTs, whereas one 12p amplicon-positive TGCT lacks expression of SOX5. The critical region of 12p over-represented in TGCTs is less than 8% of the total length of the short arm of chromosome 12. It will be helpful in the identification of the gene(s) involved in TGCT-development.

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