• Molecular diagnosis
• SS18-SSX fusion gene
• SWI/SNF complex
• Synovial sarcoma
• Therapeutic advances

• Animals
• Humans
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Oncogene Proteins, Fusion/genetics
• Oncogene Proteins, Fusion/metabolism
• Sarcoma, Synovial/genetics
• Sarcoma, Synovial/therapy
• Sarcoma, Synovial/pathology
• Sarcoma, Synovial/metabolism
• Signal Transduction/genetics

• Cancer-testis antigen
• Glioma
• Immunotherapy
• Prognosis

• NHXXRCXM202351 the Hainan Province "South China Sea Rising Star" Science and Technology Innovation Talent Platform Project
• 821MS137 the Hainan Provincial Natural Science Foundation of China
• ZDYF2022SHFZ088 the Finance science and technology project of Hainan province
• 82060456 the National Nature Science Foundation of China
• the Hainan Province “South China Sea Rising Star” Science and Technology Innovation Talent Platform Project
• Hainan Province Clinical Medical Center

• EWSR1
• RNA-based next-generation sequencing
• SSX3
• round cell
• sarcoma
• undifferentiated
• undifferentiated sarcoma of bone

• Female
• Humans
• Adult
• In Situ Hybridization, Fluorescence
• Sarcoma/genetics
• Sarcoma/pathology
• Sarcoma, Ewing/genetics
• Sarcoma, Ewing/pathology
• Transcription Factors/genetics
• Soft Tissue Neoplasms/genetics
• Gene Fusion
• Biomarkers, Tumor/genetics
• Oncogene Proteins, Fusion/genetics
• RNA-Binding Protein EWS/genetics

• P30 CA008748 NCI NIH HHS
• P50 CA217694 NCI NIH HHS

• BAF
• Epigenetics
• epithelioid sarcoma
• soft tissue sarcoma
• synovial sarcoma

• Humans
• Sarcoma, Synovial/drug therapy
• Sarcoma, Synovial/genetics
• Epigenesis, Genetic
• Neurofibrosarcoma
• Sarcoma/drug therapy
• Sarcoma/genetics
• Soft Tissue Neoplasms/drug therapy
• Soft Tissue Neoplasms/genetics

• 5-aza-2′-deoxycytidine
• SSX1
• SSX2
• SSX3
• colon cancer
• expression
• trichostatin

• 2-17-01-001-0069 This work was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdul-Aziz City for Science and Technology, Kingdom of Saudi Arabia,

• AlphaFold2
• CRISPRi
• HAP1 cells
• KRAB
• Latimeria chalumnae
• PRDM9
• SSX
• TRIM28
• ZNF10/KOX1
• coelacanth
• repression
• transcription

• Amino Acid Sequence
• Animals
• Binding Sites
• Conserved Sequence
• Evolution, Molecular
• Gain of Function Mutation
• Histone-Lysine N-Methyltransferase/chemistry
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Humans
• Invertebrates/metabolism
• Kruppel-Like Transcription Factors/chemistry
• Kruppel-Like Transcription Factors/genetics
• Models, Molecular
• Protein Conformation, alpha-Helical
• Protein Domains
• Repressor Proteins/chemistry
• Repressor Proteins/genetics
• Tripartite Motif-Containing Protein 28/metabolism

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers.

Sandhu et al. report that the synaptonemal complex (SC) protein, TEX12, localises to centrosomes independently of the SC during meiosis. They also show that it provokes centrosome amplification in somatic cells, a pathology associated with cancer development.

• gene fusion
• synovial sarcoma
• undifferentiated small round cell sarcoma

• OCT3/4
• SSX
• c-KIT
• seminoma
• spermatocytic
• testis

• Antibody therapy
• Biomarker
• CAR
• Cancer/testis antigens
• Immunotherapy
• TCR
• Vaccine

• Animals
• Antigens, Neoplasm/metabolism
• Antigens, Neoplasm/therapeutic use
• Cancer Vaccines
• Humans
• Immunotherapy/methods
• Vaccine Development
• mRNA Vaccines

• P42 ES027725 NIEHS NIH HHS

• Polycomb complex
• SS18–SSX
• SWI/SNF complex
• Synovial sarcoma
• chromatin modulation
• neoplastic pathways

• UL1 TR003167 NCATS NIH HHS

The stability of pericentromeric heterochromatin is maintained by repressive epigenetic control mechanisms, and failure to maintain this stability may cause severe diseases such as immune deficiency and cancer. Thus, deeper insight into the epigenetic regulation and deregulation of pericentromeric heterochromatin is of high priority. We and others have recently demonstrated that pericentromeric heterochromatin domains are often epigenetically reprogrammed by Polycomb proteins in premalignant and malignant cells to form large subnuclear structures known as Polycomb bodies. This may affect the regulation and stability of pericentromeric heterochromatin domains and/or the distribution of Polycomb factors to support tumorigeneses. Importantly, Polycomb bodies in cancer cells may be targeted by the cancer/testis-related SSX proteins to cause derepression and genomic instability of pericentromeric heterochromatin. This review will discuss the interplay between SSX and Polycomb factors in the repression and stability of pericentromeric heterochromatin and its possible implications for tumor biology.

• Pericentromeric heterochromatin
• SSX
• genomic instability
• polycomb protein

• Animals
• Centromere/metabolism
• Heterochromatin/metabolism
• Humans
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Polycomb-Group Proteins/metabolism
• Protein Binding
• Repressor Proteins/metabolism

• Cancer biomarkers
• Cancer immunotherapy
• Cancer stem cells
• Cancer-testis antigens
• Stem cells

Development of innovative immunotherapy is imperative to improve the poor survival of the nasopharyngeal carcinoma (NPC) patients. In this study, we evaluated the T cell response to melanoma-associated antigen (MAGE)-A1, MAGE-A3, or synovial sarcoma X-2 (SSX-2) in the peripheral blood of treatment-naive NPC patients. The relationship of responses among the three proteins and the human leukocyte antigen (HLA)-A types were analyzed to provide evidence of designing novel therapy.

Sixty-one NPC patients admitted into the Tumor Hospital affiliated to the Xinjiang Medical University between March 2015 and July 2016 were enrolled. Mononuclear cells were isolated from the peripheral blood before any treatment. HLA-A alleles were typed with Sanger sequence-based typing technique. The T cell response to the MAGE-A1, MAGE-A3, or SSX-2 was evaluated with the Enzyme-Linked ImmunoSpot assay. Mann-Whitney U-test was used to compare the T cell responses from different groups. Spearman's rank correlation was used to analyze the relationship of T cell responses.

HLA-A*02:01, A*02:07, and A*24:02 were the three most frequent alleles (18.9%, 12.3%, and 11.5%, respectively) among the 22 detected alleles. 31.1%, 19.7%, and 16.4% of the patients displayed MAGE-A1, MAGE-A3, or SSX-2-specific T cell response, respectively. The magnitudes of response to the three proteins were 32.5, 38.0, and 28.7 SFC/10⁶ peripheral blood mononuclear cells, respectively. The T cell response against the three proteins correlated with each other to different extent. The percentage of A*02:01 and A*24:02 carriers were significantly higher in patients responding to any of the three proteins compared to the nonresponders.

MAGE-A1, MAGE-A3, or SSX-2-specific T cell responses were detectable in a subgroup of NPC patients, the frequency and magnitude of which were correlated.

• Human Leukocyte Antigen-A
• Melanoma-Associated Antigen-A
• Nasopharyngeal Carcinoma
• Synovial Sarcoma X-2
• T Cell Response

Synovial sarcoma (SS) is genetically characterized by chromosomal translocation, which generates SYT-SSX fusion transcripts. Although SS can occur in any body part, primary gastric SS is substantially rare. Here we describe a detection of the fusion gene sequence of gastric SS in plasma cell-free DNA (cfDNA). A gastric submucosal tumor was detected in the stomach of a 27-year-old woman and diagnosed as SS. Candidate intronic primers were designed to detect the intronic fusion breakpoint and this fusion sequence was confirmed in intron 10 of SYT and intron 5 of SSX2 by genomic polymerase chain reaction (PCR) and direct sequencing. A locked nucleic acid (LNA) probe specific to the fusion sequence was designed for detecting the fusion sequence in plasma and the fusion sequence was detected in preoperative plasma cfDNA, while not detected in postoperative plasma cfDNA. This technique will be useful for monitoring translocation-derived diseases such as SS.

• Fusion gene
• Gastric synovial sarcoma
• Plasma
• Cell free DNA

• Adult
• Biomarkers, Tumor/genetics
• Biopsy
• Circulating Tumor DNA/blood
• Circulating Tumor DNA/genetics
• Circulating Tumor DNA/isolation & purification
• Female
• Gastroscopy
• Humans
• Introns/genetics
• Oncogene Proteins, Fusion/genetics
• Reverse Transcriptase Polymerase Chain Reaction
• Sarcoma, Synovial/blood
• Sarcoma, Synovial/diagnostic imaging
• Sarcoma, Synovial/genetics
• Sequence Analysis, DNA
• Stomach/diagnostic imaging
• Stomach/pathology
• Stomach Neoplasms/blood
• Stomach Neoplasms/diagnostic imaging
• Stomach Neoplasms/genetics

Prostate cancer is the most commonly diagnosed malignancy for men in the United States. Metastatic prostate cancer, the lethal form of the disease, has a life expectancy of approximately five years. Identification of factors associated with this transition to metastatic disease is crucial for future therapies. One such factor is the SSX gene family, a family of cancer/testis antigens (CTA) transcription factors which have been shown to be aberrantly expressed in other cancers and associated with the epithelial to mesenchymal transition (EMT). We have previously shown that SSX expression in prostate cancers was restricted to metastatic tissue and not primary tumors. In this study, we have identified SSX2 as the predominant SSX family member expressed in prostate cancer, and found its expression in the peripheral blood of 19 of 54 (35%) prostate cancer patients, with expression restricted to circulating tumor cells, and in 7 of 15 (47%) metastatic cDNA samples. Further, we examined SSX2 function in prostate cancer through knockdown and overexpression in prostate cancer cell lines. While overexpression had little effect on morphology or gene transcript changes, knockdown of SSX2 resulted in an epithelial morphology, increased cell proliferation, increased expression of genes involved in focal adhesion, decreased anchorage independent growth, increased invasion, and increased tumorigenicity in vivo. We conclude from these findings that SSX2 expression in prostate cancer is not a driver of EMT, but is involved in processes associated with EMT including loss of focal adhesion that may be related to tumor cell dissemination.

• CTA
• EMT
• SSX
• focal adhesion
• prostate cancer

• duplication syndrome
• intellectual disability
• microarray analysis

• PBMC
• UCA1
• cancer
• co-expression
• functional enrichment
• integrative
• lncRNA
• module
• weighted gene co-expression network

• Cancer subclassification
• Cancer/testis antigens
• Co-expression network
• DNA methylation
• Gene expression signature
• TSPY
• Y chromosome genes

• Cancer-retina antigens
• DNA methylation
• Onconeural antigens
• Recoverin
• Renal cancer

• Adolescent
• Adult
• Aortic Coarctation/genetics
• Child
• Child, Preschool
• Chromosomes, Human, X/genetics
• DNA Copy Number Variations
• Female
• Genetic Loci
• Humans
• Infant
• Male
• Middle Aged
• Pedigree
• Septins/genetics
• TRPM Cation Channels/genetics

• Genetics
• Histopathology
• SS18-SSX
• SYT
• Synovial sarcoma
• TLE1
• Translocation

The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX2_41-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-γ release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies.

• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Cell Line, Tumor
• Epitopes/genetics
• Epitopes/immunology
• HLA-A2 Antigen/immunology
• Humans
• Immunotherapy, Adoptive/methods
• Interferon-gamma/immunology
• Male
• Neoplasm Proteins/genetics
• Neoplasm Proteins/immunology
• Receptors, Antigen, T-Cell/immunology
• Repressor Proteins/genetics
• Repressor Proteins/immunology
• Testis/immunology

• Intramural NIH HHS

• SSX
• cancer/testis antigen
• immunotherapy
• lung cancer

• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• Humans
• Immunotherapy
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/therapy
• T-Lymphocytes/immunology

Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis. In patients with synovial sarcoma, specific chromosomal translocation of t(X; 18) (p11.2;q11.2) is observed, and SS18-SSX fusion protein expressed by this translocation is reported to be associated with pathogenesis. However, role of the fusion protein in the pathogenesis of synovial sarcoma has not yet been completely clarified. In this study, we focused on the localization patterns of SS18-SSX fusion protein. We constructed expression plasmids coding for the full length SS18-SSX, the truncated SS18 moiety (tSS18) and the truncated SSX moiety (tSSX) of SS18-SSX, tagged with fluorescent proteins. These plasmids were transfected in synovial sarcoma SYO-1 cells and we observed the expression of these proteins using a fluorescence microscope. The SS18-SSX fusion protein showed a characteristic speckle pattern in the nucleus. However, when SS18-SSX was co-expressed with tSSX, localization of SS18-SSX changed from speckle patterns to the diffused pattern similar to the localization pattern of tSSX and SSX. Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression. Our results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. These findings could be applied to further understand the pathogenic mechanisms, and towards the development of molecular targeting approach for synovial sarcoma.

• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Proteins/analysis
• Neoplasm Proteins/genetics
• Oncogene Proteins, Fusion/analysis
• Oncogene Proteins, Fusion/genetics
• Repressor Proteins/analysis
• Repressor Proteins/genetics
• Sarcoma, Synovial/genetics
• Sarcoma, Synovial/pathology

Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC.

Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP.

We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders.

Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function.

• lymphoblastoid cell lines
• cancer testis antigen
• dnmt1 inhibitor
• hdac inhibitor
• specific immunotherapy
• cancer vaccine

• Antigen-Presenting Cells/immunology
• Antigens, Neoplasm/analysis
• Azacitidine/pharmacology
• B-Lymphocytes/immunology
• B-Lymphocytes/virology
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Cancer Vaccines/immunology
• Cell Line, Transformed
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors
• Gene Expression Regulation, Neoplastic
• Herpesvirus 4, Human
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Hydroxamic Acids/pharmacology
• Interferon-gamma/immunology
• Melanoma
• Neoplasms/therapy
• RNA, Messenger/biosynthesis
• Telomerase/metabolism
• Telomere
• Tumor Necrosis Factor-alpha/immunology
• Valproic Acid/pharmacology
• Vorinostat

• Cell Compartmentation/drug effects
• Cell Line, Tumor
• Cell Nucleolus/drug effects
• Cell Nucleolus/metabolism
• Cell Nucleus/drug effects
• Cell Nucleus/metabolism
• Green Fluorescent Proteins/metabolism
• HSP70 Heat-Shock Proteins/metabolism
• Heat-Shock Response/drug effects
• Humans
• Hydrogen Peroxide/pharmacology
• Neoplasm Proteins/chemistry
• Neoplasm Proteins/metabolism
• Polycomb Repressive Complex 1/metabolism
• Protein Structure, Tertiary
• Protein Transport/drug effects
• Recombinant Fusion Proteins/metabolism
• Repressor Proteins/chemistry
• Repressor Proteins/metabolism
• Stress, Physiological/drug effects
• Tumor Suppressor Protein p14ARF/metabolism

Primordial germ cells (PGCs) sequentially induce specific genes required for their development. We focused on epigenetic changes that regulate PGC-specific gene expression. mil-1, Blimp1, and Stella are preferentially expressed in PGCs, and their expression is upregulated during PGC differentiation. Here, we first determined DNA methylation status of mil-1, Blimp1, and Stella regulatory regions in epiblast and in PGCs, and found that they were hypomethylated in differentiating PGCs after E9.0, in which those genes were highly expressed. We used siRNA to inhibit a maintenance DNA methyltransferase, Dnmt1, in embryonic stem (ES) cells and found that the flanking regions of all three genes became hypomethylated and that expression of each gene increased 1.5- to 3-fold. In addition, we also found 1.5- to 5-fold increase of the PGC genes in the PGCLCs (PGC-like cells) induced form ES cells by knockdown of Dnmt1. We also obtained evidence showing that methylation of the regulatory region of mil-1 resulted in 2.5-fold decrease in expression in a reporter assay. Together, these results suggested that DNA demethylation does not play a major role on initial activation of the PGC genes in the nascent PGCs but contributed to enhancement of their expression in PGCs after E9.0. However, we also found that repression of representative somatic genes, Hoxa1 and Hoxb1, and a tissue-specific gene, Gfap, in PGCs was not dependent on DNA methylation; their flanking regions were hypomethylated, but their expression was not observed in PGCs at E13.5. Their promoter regions showed the bivalent histone modification in PGCs, that may be involved in repression of their expression. Our results indicated that epigenetic status of PGC genes and of somatic genes in PGCs were distinct, and suggested contribution of epigenetic mechanisms in regulation of the expression of a specific gene set in PGCs.

SYT-SSX is the oncogene associated with synovial sarcoma (SS), a stem cell disease. SYT-SSX is thought to be responsible for sarcoma initiation and development. It interacts with components of Polycomb and SWI/SNF complexes, the two epigenetic controllers that maintain the heritable status of differentiation-specific genes in the stem/progenitor cell. Through these associations SYT-SSX is thought to alter gene expression programs by epigenetic mechanisms. Recently, we reported that SYT-SSX2 reprograms mesenchymal stem cells and myoblasts by dictating their commitment to the neural lineage while disrupting their normal differentiation. This reprogramming was due to the direct occupancy of proneural genes by the SYT-SSX2 nuclear complex. To gain a clear understanding of SYT-SSX2 control of gene expression networks, we conducted a thorough genome-wide analysis to determine the mechanism of its recruitment and identify signature sets of epigenetic markers that would predict its targeting and transcriptional activity.

SYT-SSX2 was recruited to distinct loci across all chromosomes, and an overwhelming number of Polycomb-modified sites enriched with the trimethylated histone H3 on lysine 27 (H3K27me3) formed the main recruiting module for SYT-SSX2. Not all SYT-SSX2/H3K27me3-occupied genes had altered expression, denoting the requirement for additional signals upon oncogene binding. Differential binding and epigenetic patterns distinguished upregulated and downregulated genes. Most activated genes had SYT-SSX2 sites enriched with H3K27me3 within their body or near their transcription start site (TSS) whereas a majority of downregulated genes were characterized by SYT-SSX2/H3K27me3-rich regions at long-range, or by modifications associated with transcription activation within the gene body or near the TSS. Hierarchical and functional clustering identified H3K27me3 as the dominant epigenetic marker associated with SYT-SSX2 binding and gene expression. Notably, this analysis revealed a cluster of upregulated neuronal genes densely covered by H3K27me3, consistent with programming toward the neural lineage by SYT-SSX2 observed previously.

The data analysis revealed that Polycomb complexes or their modified chromatin and their stably silenced differentiation programs seem to be the main target for SYT-SSX2, suggesting that their perturbation is at the center of tumorigenesis driven by the oncogene. Further research into this mechanism is crucial to the full understanding of SS biology.

Synovial sarcoma (SS), an aggressive type of soft tissue tumor, occurs mostly in adolescents and young adults. The origin and molecular mechanism of the development of SS remain only partially known. Over 90% of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of SS18-SSX1 or SS18-SSX2 fusion genes. In recent years, several reports describing direct and indirect interactions of SS18-SSX1/SSX2 oncoproteins have been published. These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis. Additional research efforts are required to fully explore the protein-protein interactions of SS18-SSX oncoproteins and the pathways that are regulated by these partnerships for the development of effective targeted therapy.

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack^1,2. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is enhanced in immune-compromised mice, while conversely, the capacity for such tumours to grow after transplantation into wild-type mice is reduced^2,3. However, many questions about the process of cancer immunoediting remain unanswered due, in part, to the known antigenic complexity and heterogeneity of carcinogen-induced tumours⁴. Here we have adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allowed us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbor identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice to mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens (TSAs) by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or MHCI presentation was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of TSA expression in immune surveillance, and potentially, immunotherapy.

• cancer
• cancer/testis antigens
• cell cycle progression
• meiosis
• mitosis
• seminiferous epithelial cycle
• spermatids
• spermatocytes
• spermatogenesis
• spermatogonia
• spermatogonial stem cells
• spermatozoa
• testis
• tumorigenesis

• R01 HD056034 NICHD NIH HHS
• U54 HD029990 NICHD NIH HHS

• ctl
• tumor antigens
• proteasome
• aminopeptidase
• processing

• Animals
• Antigen Presentation/immunology
• Antigens, Neoplasm/immunology
• Epitopes/immunology
• Female
• Histocompatibility Antigens Class I/immunology
• Humans
• Ligands
• Male
• Mice
• Proteasome Endopeptidase Complex/immunology
• Protein Processing, Post-Translational/immunology
• T-Lymphocytes, Cytotoxic/immunology

A genetic origin is estimated in 30% of infertile men with the common phenotypes of oligo- or azoospermia, but the pathogenesis of spermatogenic failure remains frequently obscure. To determine the involvement of Copy Number Variants (CNVs) in the origin of male infertility, patients with idiopathic severe oligozoospermia (N = 89), Sertoli-cell-only syndrome (SCOS, N = 37)) and controls with normozoospermia (N = 100) were analysed by array-CGH using the 244A/400K array sets (Agilent Technologies). The mean number of CNVs and the amount of DNA gain/loss were comparable between all groups. Ten recurring CNVs were only found in patients with severe oligozoospermia, three only in SCOS and one CNV in both groups with spermatogenic failure but not in normozoospermic men. Sex-chromosomal, mostly private CNVs were significantly overrepresented in patients with SCOS. CNVs found several times in all groups were analysed in a case-control design and four additional candidate genes and two regions without known genes were associated with SCOS (P<1×10⁻³). In conclusion, by applying array-CGH to study male infertility for the first time, we provide a number of candidate genes possibly causing or being risk factors for the men's spermatogenic failure. The recurring, patient-specific and private, sex-chromosomal CNVs as well as those associated with SCOS are candidates for further, larger case-control and re-sequencing studies.