GOLPH2 expression may serve as diagnostic marker in seminomas

ABSTRACT: BACKGROUND: GOLPH2 (Golgi phosphoprotein 2) is a novel Golgi membrane protein. Despite its unknown physiologic function, however, it has been proposed as a biomarker for hepatocellular and prostate carcinoma due to its upregulation in those cancer entities. Whether the overexpression of GOLPH2 is tumour specific or a generic parameter of malignancy and whether this finding is true for additional carcinomas has not been determined. In this study, we aimed to evaluate the expression pattern of GOLPH2 in testicular seminomas, the most common histologic subtype of testicular neoplasm. METHODS: GOLPH2 protein expression was assessed by immunohistochemistry in 69 testicular seminomas and compared to the expression rates in matching normal testicular tissue and intratubular germ cell neoplasia of unclassified type (IGCNU). In addition, a subset of Leydig cell tumours was analyzed accordingly. RESULTS: GOLPH2 was consistently overexpressed (89.9%) in seminomas. Matching non-neoplastic tissue showed weak or negative staining. The observed differences between non-neoplastic and neoplastic tissue were statistically highly significant (p < 0.001). There were no significant associations with tumour status. Interestingly, GOLPH2 was also highly expressed in the intertubular Leydig cells as well as in Leydig cell tumours. CONCLUSIONS: GOLPH2 protein is highly expressed in seminomas and in Leydig cell tumours. This study fosters the association of GOLPH2 with malignant neoplastic processes. The staining pattern is easily assessable and consistent which is a favourable property especially in clinical settings. GOLPH2 could be a novel immunohistochemical marker for the assessment of testicular neoplasms, especially against the background that in analogy to hepatocellular carcinomas complementary GOLPH2 serum levels might be helpful in detecting metastases or recurrent tumour. Therefore serum studies and analyses of GOLPH2 expression in non-seminomatous germ cell tumours are strongly warranted

The ter Mutation in the Rat Dnd1 Gene Initiates Gonadal Teratomas and Infertility in Both Genders

A spontaneous mutation leading to the formation of congenital ovarian and testicular tumors was detected in the WKY/Ztm rat strain. The histological evaluation revealed derivatives from all three germ layers, thereby identifying these tumors as teratomas. Teratocarcinogenesis was accompanied by infertility and the underlying mutation was termed ter. Linkage analysis of 58 (WKY-ter×SPRD-Cu3) F2 rats associated the ter mutation with RNO18 (LOD = 3.25). Sequencing of candidate genes detected a point mutation in exon 4 of the dead-end homolog 1 gene (Dnd1), which introduces a premature stop codon assumed to cause a truncation of the Dnd1 protein. Genotyping of the recessive ter mutation revealed a complete penetrance of teratocarcinogenesis and infertility in homozygous ter rats of both genders. Morphologically non-tumorous testes of homozygous ter males were reduced in both size and weight. This testicular malformation was linked to a lack of spermatogenesis using immunohistochemical and histological staining. Our WKY-Dnd1ter/Ztm rat is a novel animal model to investigate gonadal teratocarcinogenesis and the molecular mechanisms involved in germ cell development of both genders

Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor

The hematopoietic system provides an attractive model for studying growth factor-controlled expansion and differentiation of cells in relation to receptor routing and its consequences for signal transduction. Suppressor of cytokine signaling (SOCS) proteins regulate receptor signaling partly via their ubiquitin ligase (E3)-recruiting SOCS box domain. Whether SOCS proteins affect signaling through modulating intracellular trafficking of receptors is unknown. Here, we show that a juxtamembrane lysine residue (K632) of the granulocyte colony-stimulating factor receptor (G-CSFR) plays a key role in receptor routing and demonstrate that the effects of SOCS3 on G-CSF signaling to a major extent depend on this lysine. Mutation of K632 causes accumulation of G-CSFR in early endosomes and leads to sustained activation of signal transducer and activator of transcription 5 and ERK, but not protein kinase B. Myeloid progenitors expressing G-CSFR mutants lacking K632 show a perturbed proliferation/differentiation balance in response to G-CSF. This is the first demonstration of SOCS-mediated ubiquitination and routing of a cytokine receptor and its impact on maintaining an appropriate signaling output

Leukocyte-adjusted epigenome-wide association studies of blood from solid tumor patients

Epigenome-wide studies of DNA methylation using blood-derived DNA from cancer patients are complicated by the heterogeneity of cell types within blood and the associated cell lineage specification of DNA methylation signatures. Here, we applied a novel set of analytic approaches to assess the association between cancer case-status and DNA methylation adjusted for leukocyte variation using blood specimens from three case-control cancer studies (bladder: 223 cases, 205 controls; head and neck: 92 cases, 92 controls; and ovarian: 131 cases, 274 controls). Using previously published data on leukocyte-specific CpG loci and a recently described approach to deconvolute subject-specific blood composition, we performed an epigenome-wide analysis to examine the association between blood-based DNA methylation patterns and each of the three aforementioned solid tumor types adjusted for cellular heterogeneity in blood. After adjusting for leukocyte profile in our epigenome-wide analysis, the omnibus association between case-status and methylation was significant for all three studies (bladder cancer: P = 0.047; HNSCC: P = 0.013; ovarian cancer: P = 0.0002). Subsequent analyses revealed that CpG sites associated with cancer were enriched for transcription factor binding motifs involved with cancer-associated pathways. These results support the existence of cancer-associated DNA methylation profiles in the blood of solid tumor patients that are independent of alterations in normal leukocyte distributions. Adoption of the methods developed here will make it feasible to rigorously assess the influence of variability of normal leukocyte profiles when investigating cancer related changes in blood-based epigenome-wide association studies