Testicular Cancer

Overview

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (62)

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'.

GeneLocationAliasesNotesTopicPapers
MDM2 12q14.3-q15 HDMX, hdm2, ACTFS -MDM2 and Testicular Cancer
23
CYP19A1 15q21.1 ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM -CYP19A1 and Testicular Cancer
12
PTEN 10q23.31 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN and Testicular Cancer
12
SPRY4 5q31.3 HH17 -SPRY4 and Testicular Cancer
12
DROSHA 5p13.3 RN3, ETOHI2, RNASEN, RANSE3L, RNASE3L, HSA242976 -DROSHA and Testicular Cancer
11
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Testicular Cancer
11
DNMT3B 20q11.2 ICF, ICF1, M.HsaIIIB -DNMT3B and Testicular Cancer
9
TOP1 20q12-q13.1 TOPI -TOP1 and Testicuar Cancer
9
XIST Xq13.2 SXI1, swd66, DXS1089, DXS399E, LINC00001, NCRNA00001 -XIST and Testicular Cancer
8
CDK4 12q14 CMM3, PSK-J3 -CDK4 and Testicular Cancer
7
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2, RHEPDGFRA -PDGFRA and Testicular Cancer
6
CTAG1B Xq28 CTAG, ESO1, CT6.1, CTAG1, LAGE-2, LAGE2B, NY-ESO-1 -CTAG1B and Testicular Cancer
6
PTER 10p12 HPHRP, RPR-1 -PTER and Testicular Cancer
5
TGCT1 Xq27 -TGCT1 and Testicular Cancer
5
PDE11A 2q31.2 PPNAD2 -PDE11A and Testicular Cancer
5
HLA-DRB1 6p21.3 SS1, DRB1, DRw10, HLA-DRB, HLA-DR1B -HLA-DRB1 and Testicular Cancer
4
MAGEA4 Xq28 CT1.4, MAGE4, MAGE4A, MAGE4B, MAGE-41, MAGE-X2 -MAGEA4 and Testicular Cancer
4
CLU 8p21-p12 CLI, AAG4, APOJ, CLU1, CLU2, KUB1, SGP2, APO-J, SGP-2, SP-40, TRPM2, TRPM-2, NA1/NA2 -Clusterin and Testicular Cancer
4
FOXL2 3q23 BPES, PFRK, POF3, BPES1, PINTO -FOXL2 and Testicular Cancer
4
SOX17 8q11.23 VUR3 -SOX17 and Testicular Cancer
3
MAGEA3 Xq28 HIP8, HYPD, CT1.3, MAGE3, MAGEA6 -MAGEA3 and Testicular Cancer
3
BCL10 1p22 CLAP, mE10, CIPER, IMD37, c-E10, CARMEN -BCL10 and Testicular Cancer
3
GPER1 7p22.3 mER, CEPR, GPER, DRY12, FEG-1, GPR30, LERGU, LyGPR, CMKRL2, LERGU2, GPCR-Br -GPER and Testicular Cancer
3
TERC 3q26 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Testicular Cancer
3
CTCF 16q21-q22.3 MRD21 -CTCF and Testicular Cancer
3
SNRPN 15q11.2 SMN, PWCR, SM-D, sm-N, RT-LI, HCERN3, SNRNP-N, SNURF-SNRPN -SNRPN and Testicular Cancer
3
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Testicular Cancer
3
CDKN2D 19p13 p19, INK4D, p19-INK4D -CDKN2D and Testicular Cancer
3
CD79A 19q13.2 IGA, MB-1 -CD79A and Testicular Cancer
3
HLA-DQB1 6p21.3 IDDM1, CELIAC1, HLA-DQB -HLA-DQB1 and Testicular Cancer
2
APAF1 12q23 CED4, APAF-1 -APAF1 and Testicular Cancer
2
SLC5A5 19p13.11 NIS, TDH1 -SLC5A5 and Testicular Cancer
2
DCC 18q21.3 CRC18, CRCR1, MRMV1, IGDCC1, NTN1R1 -DCC and Testicular Cancer
2
CTCFL 20q13.31 CT27, BORIS, CTCF-T, HMGB1L1, dJ579F20.2 -CTCFL and Testicular Cancer
2
CKAP4 12q23.3 p63, CLIMP-63, ERGIC-63 -CKAP4 and Testicular Cancer
2
SCGB3A1 5q35.3 HIN1, HIN-1, LU105, UGRP2, PnSP-2 -SCGB3A1 and Testicular Cancer
2
CYP1B1 2p22.2 CP1B, GLC3A, CYPIB1, P4501B1 -CYP1B1 and Testicular Cancer
2
CYP3A4 7q21.1 HLP, CP33, CP34, CYP3A, NF-25, CYP3A3, P450C3, CYPIIIA3, CYPIIIA4, P450PCN1 -CYP3A4 and Testicular Cancer
2
MAGEB2 Xp21.3 DAM6, CT3.2, MAGE-XP-2 -MAGEB2 and Testicular Cancer
2
MIB1 18q11.2 MIB, DIP1, ZZZ6, DIP-1, LVNC7, ZZANK2 -MIB1 and Testicular Cancer
2
GSTT1 22q11.23 -GSTT1 and Testicular Cancer
2
MC2R 18p11.2 ACTHR -MC2R and Testicular Cancer
2
HLA-B 6p21.3 AS, HLAB, SPDA1 -HLA-B and Testicular Cancer
2
CYP1A2 15q24.1 CP12, P3-450, P450(PA) -CYP1A2 and Testicular Cancer
2
CYP3A5 7q21.1 CP35, PCN3, CYPIIIA5, P450PCN3 -CYP3A5 and Testicular Cancer
2
MYD88 3p22 MYD88D -MYD88 and Testicular Cancer
1
PITX1 5q31.1 BFT, CCF, POTX, PTX1, LBNBG -PITX1 and Testicular Cancer
1
FSHR 2p21-p16 LGR1, ODG1, FSHRO -FSHR and Testicular Cancer
1
CDH2 18q11.2 CDHN, NCAD, CD325, CDw325 -CDH2 and Testicular Cancer
1
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Testicular Cancer
1
CLP1 11q12.1 HEAB, hClp1 -CLP1 and Testicular Cancer
1
SOX1 13q34 -SOX1 and Testicular Cancer
1
ETV6 12p13 TEL, THC5, TEL/ABL -ETV6 and Testicular Cancer
1
CTGF 6q23.1 CCN2, NOV2, HCS24, IGFBP8 -CTGF and Testicular Cancer
1
CASC5 15q14 D40, CT29, KNL1, Spc7, hKNL-1, AF15Q14, PPP1R55, hSpc105 -CASC5 and Testicular Cancer
1
MCC 5q21 MCC1 -MCC and Testicular Cancer
1
SNX29 16p13.13-p13.12 RUNDC2A, A-388D4.1 -SNX29 and Testicular Cancer
1
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Testicular Cancer
1
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Testicular Cancer
1
PPP1R13L 19q13.32 RAI, RAI4, IASPP, NKIP1 -PPP1R13L and Testicular Cancer
1
PTPRC 1q31-q32 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

Han MH, Park SW, Do HJ, et al.
Growth and Differentiation Factor 3 Is Transcriptionally Regulated by OCT4 in Human Embryonic Carcinoma Cells.
Biol Pharm Bull. 2016; 39(11):1802-1808 [PubMed] Related Publications
Growth and differentiation factor 3 (GDF3), a mammalian-specific transforming growth factor β ligand, and OCT4, one of key stem cell transcription factors, are expressed in testicular germ cell tumors (TGCTs) as well as pluripotent stem cells. To understand the molecular mechanism by which OCT4 and GDF3 function in tumorigenesis as well as stemness, we investigated the transcriptional regulation of GDF3 mediated by OCT4 in human embryonic carcinoma (EC) NCCIT cells, which are pluripotent stem cells of TGCTs. GDF3 and OCT4 was highly expressed in undifferentiated NCCIT cells and then significantly decreased upon retinoic acid-induced differentiation in a time-dependent manner. Moreover, GDF3 expression was reduced by short hairpin RNA-mediated knockdown of OCT4 and increased by OCT4 overexpression, suggesting that GDF3 and OCT4 have a functional relationship in pluripotent stem cells. A promoter-reporter assay revealed that the GDF3 promoter (-1721-Luc) activity was significantly activated by OCT4 in a dose-dependent manner. Moreover, the minimal promoter (-183-Luc) was sufficient for OCT4-mediated transcriptional activation and provided a potential binding site for the direct interaction with OCT4. Collectively, this study provides the evidence about the regulatory mechanism of GDF3 mediated by OCT4 in pluripotent EC cells.

Flor I, Spiekermann M, Löning T, et al.
Expression of microRNAs of C19MC in Different Histological Types of Testicular Germ Cell Tumour.
Cancer Genomics Proteomics. 2016 Jul-Aug; 13(4):281-9 [PubMed] Related Publications
BACKGROUND: Testicular germ cell tumours (TGCTs) are the most common tumours in men aged from 20 to 40 years, with a steadily increasing incidence. This study aimed to characterize the expression of the miRNA cluster C19MC in TGCT and to evaluate the suitability of a C19MC miRNA as a serum biomarker.
MATERIALS AND METHODS: By quantitative reverse transcription PCR, we measured the expression of miR-517a-3p, miR-519a-3p, and miR-519c 3p in tissue samples of 25 TGCTs and the level of miR-517a-3p in serum samples obtained pre- and postoperatively from the same patients.
RESULTS: We detected a significantly higher expression of C19MC miRNAs in non-seminomas than in seminomas and in clinical stages 2 and 3 than in stage 1 in both tissue and serum samples.
CONCLUSION: miRNAs of C19MC are overexpressed in more aggressive types of TGCT, suggesting they contribute to malignancy. Furthermore, they might serve as serum biomarkers for these types of TGCT.

Boublikova L, Bakardjieva-Mihaylova V, Skvarova Kramarzova K, et al.
Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors.
Cancer Lett. 2016; 376(2):367-76 [PubMed] Related Publications
PURPOSE: Wilms tumor gene 1 (WT1), a zinc-finger transcription factor essential for testis development and function, along with other genes, was investigated for their role in the pathogenesis of testicular germ cell tumors (TGCT).
METHODS: In total, 284 TGCT and 100 control samples were investigated, including qPCR for WT1 expression and BRAF mutation, p53 immunohistochemistry detection, and massively parallel amplicon sequencing.
RESULTS: WT1 was significantly (p < 0.0001) under-expressed in TGCT, with an increased ratio of exon 5-lacking isoforms, reaching low levels in chemo-naïve relapsed TGCT patients vs. high levels in chemotherapy-pretreated relapsed patients. BRAF V600E mutation was identified in 1% of patients only. p53 protein was lowly expressed in TGCT metastases compared to the matched primary tumors. Of 9 selected TGCT-linked genes, RAS/BRAF and WT1 mutations were frequent while significant TP53 and KIT variants were not detected (p = 0.0003).
CONCLUSIONS: WT1 has been identified as a novel factor involved in TGCT pathogenesis, with a potential prognostic impact. Distinct biologic nature of the two types of relapses occurring in TGCT has been demonstrated. Differential mutation rate of the key TGCT-related genes has been documented.

Cornejo KM, Cheng L, Church A, et al.
Chromosome 12p abnormalities and IMP3 expression in prepubertal pure testicular teratomas.
Hum Pathol. 2016; 49:54-60 [PubMed] Related Publications
Although the histologic appearance of pure testicular teratomas (PTTs) is similar in children and adults, the prognosis is dramatically different. Prepubertal PTTs are rare, with a benign clinical course, whereas the adult cases typically have malignant outcomes. Chromosome 12p abnormalities are seen in most adult testicular germ cell tumors but have not been found in prepubertal PTTs. IMP3 is an oncofetal protein that is highly expressed in many malignancies. Recently, we demonstrated IMP3 is expressed in adult mature testicular teratomas but not in mature ovarian teratomas. The aim of this study was to evaluate prepubertal PTTs for chromosome 12p abnormalities and expression of IMP3. A total of 11 cases (excision, n=1; orchiectomy, n=10) were obtained from the surgical pathology archives of 2 large medical centers (1957-2013). All 11 cases were investigated for isochromosome 12p and 12p copy number gain using interphase fluorescence in situ hybridization analysis and were examined by immunohistochemistry for IMP3 expression. Patients ranged in age from 0.9 to 7.0 (mean, 2.4) years. A positive immunohistochemical stain for IMP3 (cytoplasmic staining) was identified in 5 (46%) of 11 cases. Isochromosome 12p was detected in 2 cases (18%) that also expressed IMP3. Somatic copy number alterations of 12p were not observed (0%). We are the first to describe 12p abnormalities and IMP3 expression in prepubertal PTTs. Our data demonstrate a small subset of PTTs harbor typical molecular alterations observed in adult testicular germ cell tumors. Although prepubertal PTTs are considered to be benign neoplasms, it may be a heterogeneous group.

Bartsch G, Jennewein L, Harter PN, et al.
Autophagy-associated proteins BAG3 and p62 in testicular cancer.
Oncol Rep. 2016; 35(3):1629-35 [PubMed] Related Publications
Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue micro- arrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco‑regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue.

Chapuy B, Roemer MG, Stewart C, et al.
Targetable genetic features of primary testicular and primary central nervous system lymphomas.
Blood. 2016; 127(7):869-81 [PubMed] Free Access to Full Article Related Publications
Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.

Hoff AM, Alagaratnam S, Zhao S, et al.
Identification of Novel Fusion Genes in Testicular Germ Cell Tumors.
Cancer Res. 2016; 76(1):108-16 [PubMed] Free Access to Full Article Related Publications
Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men ages 15 to 44 years. Embryonal carcinomas (EC) comprise a subset of TGCTs that exhibit pluripotent characteristics similar to embryonic stem (ES) cells, but the genetic drivers underlying malignant transformation of ECs are unknown. To elucidate the abnormal genetic events potentially contributing to TGCT malignancy, such as the existence of fusion genes or aberrant fusion transcript expression, we performed RNA sequencing of EC cell lines and their nonmalignant ES cell line counterparts. We identified eight novel fusion transcripts and one gene with alternative promoter usage, ETV6. Four out of nine transcripts were found recurrently expressed in an extended panel of primary TGCTs and additional EC cell lines, but not in normal parenchyma of the testis, implying tumor-specific expression. Two of the recurrent transcripts involved an intrachromosomal fusion between RCC1 and HENMT1 located 80 Mbp apart and an interchromosomal fusion between RCC1 and ABHD12B. RCC1-ABHD12B and the ETV6 transcript variant were found to be preferentially expressed in the more undifferentiated TGCT subtypes. In vitro differentiation of the NTERA2 EC cell line resulted in significantly reduced expression of both fusion transcripts involving RCC1 and the ETV6 transcript variant, indicating that they are markers of pluripotency in a malignant setting. In conclusion, we identified eight novel fusion transcripts that, to our knowledge, are the first fusion genes described in TGCT and may therefore potentially serve as genomic biomarkers of malignant progression.

Spiller CM, Gillis AJ, Burnet G, et al.
Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors.
Mol Oncol. 2016; 10(4):526-37 [PubMed] Related Publications
Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management.

Cheung HH, Yang Y, Lee TL, et al.
Hypermethylation of genes in testicular embryonal carcinomas.
Br J Cancer. 2016; 114(2):230-6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation.
METHODS: To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages (stage I and stage III) of divergent invasiveness. Non-cancerous testicular tissues were included. Expression of a number of hypermethylated genes were examined by quantitative RT-PCR and immunohistochemistry (IHC).
RESULTS: A total of 1167 tumour-hypermethylated differentially methylated regions (DMRs) were identified across the genome. Among them, 40 genes/ncRNAs were found to have hypermethylated promoters. Quantitative RT-PCR confirmed downregulation of 8 out of 9 of the genes. Among the confirmed genes, five were sex-linked genes, including X-linked genes STAG2, SPANXD/E and MIR1184, and Y-linked genes RBMY1A1/1B/1D and FAM197Y2P. RBMY1A is a testis-specific gene for spermatogenesis. RNF168 and USP13 are potential tumour suppressors. Expression of RBMY1A was lost in EC and seminoma as documented in the Protein Atlas. We confirmed downregulation of USP13 in EC by IHC.
CONCLUSIONS: Our genome-wide analysis of testicular EC identified methylation changes in several previously unknown genes. This may provide insight of crosstalk between normal germ cell development and carcinogenesis.

Ling H, Krassnig L, Bullock MD, Pichler M
MicroRNAs in Testicular Cancer Diagnosis and Prognosis.
Urol Clin North Am. 2016; 43(1):127-34 [PubMed] Related Publications
Testicular cancer processes a unique and clear miRNA expression signature. This differentiates testicular cancer from most other cancer types, which are usually more ambiguous when assigning miRNA patterns. As such, testicular cancer may represent a unique cancer type in which miRNAs find their use as biomarkers for cancer diagnosis and prognosis, with a potential to surpass the current available markers usually with low sensitivity. In this review, we present literature findings on miRNAs associated with testicular cancer, and discuss their potential diagnostic and prognostic values, as well as their potential as indicators of drug response in patients with testicular cancer.

Cárcano FM, Vidal DO, van Helvoort Lengert A, et al.
Hotspot TERT promoter mutations are rare events in testicular germ cell tumors.
Tumour Biol. 2016; 37(4):4901-7 [PubMed] Related Publications
The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at -245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.

Litchfield K, Holroyd A, Lloyd A, et al.
Identification of four new susceptibility loci for testicular germ cell tumour.
Nat Commun. 2015; 6:8690 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 × 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 × 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 × 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 × 10(-9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development.

Gonzalez-Exposito R, Merino M, Aguayo C
Molecular biology of testicular germ cell tumors.
Clin Transl Oncol. 2016; 18(6):550-6 [PubMed] Related Publications
Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies.

Litchfield K, Mitchell JS, Shipley J, et al.
Polygenic susceptibility to testicular cancer: implications for personalised health care.
Br J Cancer. 2015; 113(10):1512-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic risk profiling in combination with other diagnostic tools.
METHODS: We compared the number of cases potentially detectable in the population under a number of screening models. The polygenic risk scoring (PRS) model was assumed to have a log-normal relative risk distribution across the 19 currently known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme.
RESULTS: The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having a nine-fold increased TGCT risk compared with the population median. Results from population-screening simulations only achieved a maximal positive predictive value (PPV) of 60%, highlighting broader clinical factors that challenge such strategies, not least the rare nature of TGCT. In terms of future improvements, heritability estimates suggest that a significant number of additional genetic risk factors for TGCT remain to be discovered, identification of which would potentially yield improvement of the PPV to 80-90%.
CONCLUSIONS: While personalised screening models may offer enhanced TGCT risk discrimination, presently the case for population-level testing is not compelling. However, future advances, such as more routine generation of whole genome data is likely to alter the landscape. More targeted screening programs may plausibly then offer clinical benefit, particularly given the significant survivorship issues associated with the successful treatment of TGCT.

Pathak A, Stewart DR, Faucz FR, et al.
Rare inactivating PDE11A variants associated with testicular germ cell tumors.
Endocr Relat Cancer. 2015; 22(6):909-17 [PubMed] Related Publications
Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.

Gilbert DC, Al-Saadi R, Thway K, et al.
Defining a New Prognostic Index for Stage I Nonseminomatous Germ Cell Tumors Using CXCL12 Expression and Proportion of Embryonal Carcinoma.
Clin Cancer Res. 2016; 22(5):1265-73 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Up to 50% of patients diagnosed with stage I nonseminomatous germ cell tumors (NSGCTs) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up front. Late toxicities from chemotherapy are increasingly recognized. Based on a potential biologic role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse.
EXPERIMENTAL DESIGN: Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma), and MIB1 staining for proliferation in formalin-fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCTs.
RESULTS: TE08/TE22 trial patients had a 76.4% 2-year relapse-free rate, and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test P = 0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma, and VI defines three prognostic groups that were independently validated.
CONCLUSIONS: CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy.

Bremmer F, Schallenberg S, Jarry H, et al.
Role of N-cadherin in proliferation, migration, and invasion of germ cell tumours.
Oncotarget. 2015; 6(32):33426-37 [PubMed] Free Access to Full Article Related Publications
Germ cell tumors (GCTs) are the most common malignancies in young men. Most patients with GCT can be cured with cisplatin-based combination chemotherapy, even in metastatic disease. In case of therapy resistance, prognosis is usually poor. We investigated the potential of N-cadherin inhibition as a therapeutic strategy. We analyzed the GCT cell lines NCCIT, NTERA-2, TCam-2, and the cisplatin-resistant sublines NCCIT-R and NTERA-2R. Effects of a blocking antibody or siRNA against N-cadherin on proliferation, migration, and invasion were investigated. Mouse xenografts of GCT cell lines were analyzed by immunohistochemistry for N-cadherin expression. All investigated GCT cell lines were found to express N-cadherin protein in vitro and in vivo. Downregulation of N-cadherin in vitro leads to a significant inhibition of proliferation, migration, and invasion. N-cadherin-downregulation leads to a significantly higher level of pERK. N-cadherin-inhibition resulted in significantly higher rates of apoptotic cells in caspase-3 staining. Expression of N-cadherin is preserved in cisplatin-resistant GCT cells, pointing to an important physiological role in cell survival. N-cadherin-downregulation results in a significant decrease of proliferation, migration, and invasion and stimulates apoptosis in cisplatin-naive and resistant GCT cell lines. Therefore, targeting N-cadherin may be a promising therapeutic approach, particularly in cisplatin-resistant, therapy refractory and metastatic GCT.

Conlon N, Schultheis AM, Piscuoglio S, et al.
A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors.
Mod Pathol. 2015; 28(12):1603-12 [PubMed] Free Access to Full Article Related Publications
Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.

Wang Y, Chen J, Yang W, et al.
The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors.
Neoplasia. 2015; 17(8):650-60 [PubMed] Free Access to Full Article Related Publications
DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.

Oishi N, Kondo T, Nakazawa T, et al.
High prevalence of the MYD88 mutation in testicular lymphoma: Immunohistochemical and genetic analyses.
Pathol Int. 2015; 65(10):528-35 [PubMed] Related Publications
The activating mutation of MYD88 has been identified in diffuse large B-cell lymphoma (DLBCL). We investigated the mutational status and both the gene amplification and protein expression of MYD88 in 23 cases of testicular DLBCL. To detect the MYD88 mutations, we employed the allele-specific PCR and Sanger sequencing. MYD88 gene amplification and protein expression were analyzed by quantitative PCR and by immunohistochemistry, respectively. There were 17 cases of primary testicular DLBCL: 94% (16/17) exhibited a non-Germinal center B-cell (non-GCB) subtype, 82% (14/17) showed the MYD88 L265P, and 65% (11/17) had intense expression of MYD88. When compared with normal lymph nodes, the MYD88 is significantly amplified in primary testicular DLBCL. However, the amplification status showed no correlation with its mutational status or protein expression. Moreover, neither the MYD88 mutational status nor the expression pattern affected overall survival. Six cases were secondary testicular DLBCL with an 83% (5/6) and an 80% (4/5) incidence of the non-GCB subtype and of the MYD88 L265P, respectively. In conclusion, we demonstrated a high prevalence of the non-GCB subtype and the common MYD88 L265P in both primary and secondary testicular DLBCL. Our data suggest that the MYD88 mutation is a fairly consistent genetic feature in testicular DLBCL.

Litchfield K, Thomsen H, Mitchell JS, et al.
Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches.
Sci Rep. 2015; 5:13889 [PubMed] Free Access to Full Article Related Publications
A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors. Recent genome-wide association studies (GWAS) have successfully identified a number of common SNPs associated with TGCT. It is however, unclear how much common variation there is left to be accounted for by other, yet to be identified, common SNPs and what contribution common genetic variation makes to the heritable risk of TGCT. We approached this question using two complimentary analytical techniques. We undertook a population-based analysis of the Swedish family-cancer database, through which we estimated that the heritability of TGCT at 48.9% (CI:47.2%-52.3%). We also applied Genome-Wide Complex Trait Analysis to 922 cases and 4,842 controls to estimate the heritability of TGCT. The heritability explained by known common risk SNPs identified by GWAS was 9.1%, whereas the heritability explained by all common SNPs was 37.4% (CI:27.6%-47.2%). These complementary findings indicate that the known TGCT SNPs only explain a small proportion of the heritability and many additional common SNPs remain to be identified. The data also suggests that a fraction of the heritability of TGCT is likely to be explained by other classes of genetic variation, such as rare disease-causing alleles.

Schultz KA, Harris A, Messinger Y, et al.
Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.
Fam Cancer. 2016; 15(1):105-10 [PubMed] Free Access to Full Article Related Publications
Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.

Rounge TB, Furu K, Skotheim RI, et al.
Profiling of the small RNA populations in human testicular germ cell tumors shows global loss of piRNAs.
Mol Cancer. 2015; 14:153 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Small non-coding RNAs play essential roles in gene regulation, however, the interplay between RNA groups, their expression levels and deregulations in tumorigenesis requires additional exploration. In particular, a comprehensive analysis of microRNA (miRNA), PIWI-interacting RNAs (piRNAs), and tRNA-derived small RNAs in human testis and testicular germ cell tumor (TGCT) is lacking.
RESULTS: We performed small RNA sequencing on 22 human TGCT samples from 5 histological subtypes, 3 carcinoma in situ, and 12 normal testis samples. miRNA was the most common group among the sequences 18-24 nt in length and showed histology-specific expression. In normal samples, most sequences 25-31 nucleotides in length displayed piRNA characteristics, whereas a large proportion of the sequences 32-36 nt length was derived from tRNAs. Expression analyses of the piRNA population demonstrated global loss in all TGCT subtypes compared to normal testis. In addition, three 5' small tRNA fragments and 23 miRNAs showed significant (p < 10(-6)) differential expression in cancer vs normal samples.
CONCLUSIONS: We have documented significant changes in the small RNA populations in normal adult testicular tissue and TGCT samples. Although components of the same pathways might be involved in miRNA, piRNA and tRNA-derived small RNA biogenesis, our results showed that the response to the carcinogenic process differs between these pathways, suggesting independent regulation of their biogenesis. Overall, the small RNA deregulation in TGCT provides new insight into the small RNA interplay.

La Starza R, Nofrini V, Pierini T, et al.
Molecular Cytogenetics Detect an Unbalanced t(2;13)(q36;q14) and PAX3-FOXO1 Fusion in Rhabdomyosarcoma With Mixed Embryonal/Alveolar Features.
Pediatr Blood Cancer. 2015; 62(12):2238-41 [PubMed] Related Publications
Distinguishing between alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) is crucial because treatment and prognosis are different. We describe a case of paratesticular rhabdomyosarcoma (RMS), which was classified as mixed ERMS/ARMS. Fluorescence in situ hybridization (FISH) detected losses of 3'PAX3 and 5'FOXO1, suggesting they had undergone an unbalanced rearrangement that probably produced the PAX3-FOXO1 fusion. Double-color FISH and reverse transcription-polymerase chain reaction (RT-PCR) revealed PAX3-FOXO1, which is characteristic of high-risk RMS. This finding highlights the importance of supplementing histology with genetics so that atypical RMS is appropriately classified and patients are correctly stratified and treated.

Maqdasy S, Bogenmann L, Batisse-Lignier M, et al.
Leydig cell tumor in a patient with 49,XXXXY karyotype: a review of literature.
Reprod Biol Endocrinol. 2015; 13:72 [PubMed] Free Access to Full Article Related Publications
49,XXXXY pentasomy or Fraccaro's syndrome is the most severe variant of Klinefelter's syndrome (KS) affecting about 1/85000 male births. The classical presentation is the triad: mental retardation, hypergonadotropic hypogonadism and radio ulnar synostosis. Indeed, the reproductive function of Fraccaro's syndrome is distinguished from KS. Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants.We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism. Chromosomal pentasomy was confirmed since infancy. Bilateral orchidectomy revealed a unilateral well-circumscribed Leydig cell tumor associated with bilateral Leydig cell hyperplasia.Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side. The histological destructions in 49,XXXXY testes and hypogonadism are more profound than in Klinefelter patients, with early Sertoli, Leydig and germ cell destruction. Furthermore, the risk of Leydigioma development in KS and its variants remains a dilemma. We believe that the risk of Leydigioma is much higher in KS than the general population. By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation.

Zhu J, Zhang S, Zhu L, et al.
Primary testicular Ph-positive B lymphoblastic lymphoma: an unusual presentation and review.
Cancer Biol Ther. 2015; 16(8):1122-7 [PubMed] Free Access to Full Article Related Publications
Primary testicular B-lymphoblastic lymphoma is a rare entity. Primary testicular Ph-positive B lymphoblastic lymphoma was not reported before. We reported a 27-year-old man with primary testicular Ph-positive B lymphoblastic lymphoma, for which fluorescent in-situ hybridization (FISH) for the Philadelphia chromosome was not performed at the initial hospitalization. The patient showed manifestation of Ph-positive acute lymphoblastic leukemia at relapse. In this report, we reviewed the current literature about primary testicular B-lymphoblastic lymphoma, Ph-positive lymphoma and Ph-positive clone evolution. This report has 3 meanings. First: This is first report on primary testicular Ph-positive B lymphoblastic lymphoma. Second: This shows the importance of cytogenics for lymphoma treatment. Third: This implies Philadelphia-positive subclone evolution.

Bazalitska SV, Romanenko AM, Sakalo VS, Sakalo AV
[IMMUNOHISTOCHEMICAL EXPRESSION OF UBIQUITIN PROTEIN IN PERITUMORAL TISSUE OF PATIENTS WITH TESTICULAR GERM CELL TUMORS].
Lik Sprava. 2015 Jan-Mar; (1-2):48-55 [PubMed] Related Publications
For the purpose of definition of features immunohistochemical expression of protein Ubiquitin in peritumoral testicular tissue, which can be characterised as precancerous changes, the 40 patients with testicular germ cell tumors are investigated. In peritumoral testicular tissue in patients with disturbance of spermatogenesis. which make 95 %, it is taped: intensifying in seminiferous tubules of ubiquitination processes, testifying about intensive proteolysis of considerable quantity of the damaged intracellular proteins, occurrence of atypical germ cells (TIN), which differ from normal spermatogenesis cells authentically lower of nuclear and cytoplasmatic expression of protein Ubiquitin, and also disturbance of ubiquitination processes in Leydig cells in the form of intensifying of cytoplasmatic expression and total disappearance of nuclear expression of protein Ubiquitin. The received results testify to the important role of structural and functional disturbances of ubiquitin-proteolysis system components at the initial stages of testicular tissue carcinogenesis.

Lawaetz AC, Almstrup K
Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer.
Biomol Concepts. 2015; 6(3):219-27 [PubMed] Related Publications
Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men.

Dendrinos ML, Smorgick N, Marsh CA, et al.
Occurrence of Gonadoblastoma in Patients with 45,X/46,XY Mosaicism.
J Pediatr Adolesc Gynecol. 2015; 28(3):192-5 [PubMed] Related Publications
STUDY OBJECTIVE: To estimate the overall frequency of gonadal tumors in patients with 45,X/46,XY mosaicism who underwent gonadectomy and to determine whether the degree of external masculinization or the location of gonads were associated with the presence of gonadal tumor.
DESIGN: Retrospective study of patients with karyotype of 45,X/46,XY or variant who received care at the study institution between 1995 and 2012.
SETTING: University of Michigan Health System (Ann Arbor, Michigan), a tertiary care academic center.
PARTICIPANTS: Sixteen patients with karyotype of 45,X/46,XY who underwent gonadectomy.
INTERVENTIONS: None.
MAIN OUTCOME MEASURE: Presence of pathology-confirmed gonadal tumor.
RESULTS: In patients who underwent bilateral gonadectomy, gonadoblastomas were detected in 36.4% (4 of 11), and all were identified in patients with normal female external genitalia (4 of 8 [50.0%]). Abdominal gonads were associated with a nonsignificant increase in rate of gonadal tumor compared with inguinal or scrotal gonads. No malignant tumors were identified.
CONCLUSION: The overall rate of gonadoblastoma was higher than previously reported. The high rate of gonadoblastoma in patients with female external genitalia and the lack of gonadal function support continuing the standard of care of practice of prophylactic gonadectomy in this patient population.

Zhang M, He AB, Cai ZM, Wu S
[Updated genomics of testicular germ cell tumor].
Zhonghua Nan Ke Xue. 2015; 21(4):363-70 [PubMed] Related Publications
Testicular germ cell tumor (TGCT) is a most common testicular malignancy with an increasing incidence, and its pathogenesis and mechanisms are not yet clear. The next generation sequencing has become the main tool to uncover the underlying mechanisms of TGCT. The differential gene expressions, gene mutation, predisposing gene-dominated signaling pathways, and changes of the relevant genes in the sex chromosome are largely involved in the occurrence and development of TGCT. Studies on the genomics of TGCT contribute a lot to identifying the pivotal pathogenic genes and paving a theoretical ground for the early screening and targeted therapy of TGCT. This paper summarizes the advances in the studies of the genomics of TGCT so as to reveal thetmechanisms of the disease at the genetic level.

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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