Familial germ cell tumor

Familial testicular germ cell tumors are well known in literature. Only few cases are reported where both brother and sister of the same family suffered from germ cell malignancies. We present a family where the proband is a survivor of ovarian dysgerminoma stage IA. Her elder male sibling became acutely ill and was detected to have disseminated testicular malignancy with grossly elevated markers and vegetations in the mitral valve leaflets. Despite all measures he could not be saved. Presence of germ cell malignancies in the siblings of different sex in the same family points toward a genetic susceptibility. Literature review revealed only six similar cases. A discussion regarding the rare occurrence of familial germ cell malignancies with the affected family members may be worthwhile.     

De novo malignant solitary fibrous tumor of the kidney

Background

To study the expression of MK-1 and RegIV and to detect their pathological significances in benign and malignant lesions of gallbladder.

Methods

The expression of MK-1 and RegIV was detected by immunohistochemical method in paraffin-embedded sections of surgical resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenomatous polyp (n = 15), and chronic cholecystitis (n = 35).

Results

The positive rate of MK-1 or RegIV expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (X² _MK-1 = 18.76, P < 0.01; X² _RegIV = 9.92, P < 0.01), denomatous polyp (X² _MK-1 = 9.49, P < 0.01; X² _RegIV = 8.59, P < 0.01) and chronic cholecystitis (X² _MK-1 = 24.11, P < 0.01; X² _RegIV = 19.24, P < 0.01). The positive cases of MK-1 and/or RegIV in the benign lesions showed moderately- or severe-atypical hyperplasia of gallbladder epitheli. The positive rates of MK-1 were significantly higher in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (P < 0.05 or P < 0.01). On the contrary, the positive rates of RegIV were significantly lower in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (P < 0.05 or P < 0.01). Univariate Kaplan-Meier analysis showed that decreased expression of MK-1 (P = 0.09) or increased expression of RegIV (P = 0.003) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MK-1 (P = 0.033) and increased expression of RegIV (P = 0.008) was an independent prognostic predictor in gallbladder adenocarcinoma.

Conclusions

The expression of MK-1 and/or RegIV might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.     

New insights into germ cell tumor formation.

Recent years have witnessed a number of new findings with significant implications for our understanding of the development of germ cell tumors. This communication reviews some of these recent insights with an emphasis on mechanisms that may convert a germ cell into a tumor cell. Three aspects are discussed in this review: (1) the early origin of germ cell tumors from primordial germ cells through an aberrant mitosis-to-meiosis switch; (2) errors during meiosis, which promote tumorigenic transformation of germ cells; and (3) the role of small RNAs such as oncomirs (miRNAs) and oncopirs (piRNAs) in germ cell tumor formation. Since much has been learned using a variety of organismal models, data obtained in experiments with mice, nematodes, fruit flies, and human data will be considered. Only exemplary references are included.     

De novo mutational signature discovery in tumor genomes using SparseSignatures

Cancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or “mutational signatures”. Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates a user-specified background signature, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using a variety of standard metrics. We then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms and are strongly associated with patient clinical features.     

De novo del(6)(q25) associated with macular degeneration

An eight-month-old girl with a de novo del(6)(q25) is described. She and other previous cases of 6q deletion showed concordance for developmental retardation associated with multiple unspecific congenital abnormalities, which do not yet allow the delineation of a syndrome. However, bilateral macular degeneration was found in the proposita and had been observed in another similar case, so it probably represents a distinctive feature of 6q terminal monosomy. This observation also suggests the existence of a dominant macular degeneration locus within 6q25----qter.     

A case of Klinefelter's syndrome associated with hypothalamic-pituitary dysfunction caused by an intracranial germ cell tumor

A 17 year-old boy was admitted to the hospital because of thirst, polyuria (5-61/day), delayed sexual development and muscle weakness. He appeared obese, had an eunuchoidal body habitus and was excessively tall. Chromosomal analysis revealed a 47XXY karyotype. Serum cortisol was 1.3 microgram/dl, LH, 10.4 mIU/ml, FSH, 2.0 mIU/ml, and testosterone, 10 ng/dl. Endocrinological dynamic tests indicated diabetes insipidus and hypopituitarism of a hypothalamic type. Brain CT disclosed the existence of a tumor shadow around the calcified pineal body, extending towards the suprasellar region. Replacement therapy with glucocorticoid and DDAVP was started. The patient complained of a headache and plasma AFP and hCG concentrations were 868 ng/ml and 68.6 IU/ml respectively. A hCG- and AFP- producing germ cell tumor was suspected and radiation therapy with 60Co was performed. Plasma AFP and hCG were decreased with significant clinical improvement. Soon after irradiation, he started to complain of a headache and had elevated AFP and hCG levels. Right hemiparesis and unconsciousness suddenly appeared and he died of left thalamic bleeding. This is the first case of Klinefelter's syndrome associated with intracranial germ cell tumor. Plasma testosterone levels fluctuated in parallel with the change in plasma hCG levels. This shows that the Leydig cells in this patient could respond to some extent to tumor-producing hCG.     

De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature

Background

Human height is a complex trait with a strong genetic basis. Recently, a significant association between rare copy number variations (CNVs) and short stature has been identified, and candidate genes in these rare CNVs are being explored. This study aims to evaluate the association between mutations in ARID1B gene and short stature, both the syndromic and non-syndromic form.

Results

Based on a case-control study of whole genome chromosome microarray analysis (CMA), three overlapping CNVs were identified in patients with developmental disorders who exhibited short stature. ARID1B, a causal gene for Coffin Siris syndrome, is the only gene encompassed by all three CNVs. A following retrospective genotype-phenotype analysis based on a literature review confirmed that short stature is a frequent feature in those Coffin-Siris syndrome patients with ARID1B mutations. Mutation screening of ARID1B coding regions was further conducted in a cohort of 48 non-syndromic short stature patients,andfour novel missense variants including two de novo mutations were found.

Conclusion

These results suggest that haploinsufficient mutations of ARID1B are associated with syndromic short stature including Coffin-Siris syndrome and intellectual disability, while rare missense variants in ARID1B are associated with non-syndromic short stature. This study supports the notion that mutations in genes related to syndromic short stature may exert milder effect and contribute to short stature in the general population.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1898-1) contains supplementary material, which is available to authorized users.     

‘De novo’ centrioles originate at sites associated with annulate lamellae in sea-urchin eggs

Hypertonic stress stimulates the formation of new centrioles in sea-urchin eggs. Those centrioles which appear away from the nuclear surface originate exclusiveJy at sites associated with annulate lamellae. Although apparent when nascent centrioles become visible, the annulate lamellar association is gradually lost as nascent forms mature into centrioles.     

Differentiation of human germ cell tumor cells

Human germ cell tumors are an excellent model for investigating the mechanism of human early embryogenesis as well as cellular differentiation. Three human EC cell lines, NCR-G 2, 3 and 4 were newly established from testicular mixed embryonal carcinomas in vitro, G3 and G4 cells were capable of somatic cell differentiation. The G3 cells demonstrated the most noticeable antigenetical changes with the administration of retinoic acid. SSEA-1 appeared on some cells whereas expression of HLA-A, B, C as well as 2H2, 2D7 and 5D4 antigens tended to be reduced in G3 cell line. 2H2, 2D7 and 5D4 antigens which we recently produced were immature human EC specific cell surface antigens, defined by mouse monoclonal antibodies, obtained immunization with G2 cells. The production of hCG, high molecular weight cytokeratin and intercellular matrices such as type IV collagen and laminin were inducible in G3 cells. Thus, G3 cells are thought to be one of the most pluripotent human EC cells. These findings clearly indicate that the EC cell lines we established provide an opportunity to study differentiation mechanism of human germ cell tumors and also human somatic cells.     

De novo (11;13) translocation.

A male infant is described with unusual facial appearance, clubfeet, and moderate hydrocephalus internus without obvious deficiency in mental and physical development. Cytogenetic studies revealed a karyotype of 45,XY,--C,--D,+t(C;D). A chromosome 11 and a 13 are involved in the formation of the translocation chromosome. The long arm of chromosome 13 is linearly attached to the end of the long arm of chromosome 11 (tandem translocation). Chromosome material of the distal part of the long arm of chromosome 11, as well as the short arm plus the centromere of chromosome 13 seem to have been lost.     

De novo proteins as models of radical enzymes.

Catalytically essential side-chain radicals have been recognized in a growing number of redox enzymes. Here we present a novel approach to study this class of redox cofactors. Our aim is to construct a de novo protein, a radical maquette, that will provide a protein framework in which to investigate how side-chain radicals are generated, controlled, and directed toward catalysis. A tryptophan and a tyrosine radical maquette, denoted alpha(3)W(1) and alpha(3)Y(1), respectively, have been synthesized. alpha(3)W(1) and alpha(3)Y(1) contain 65 residues each and have molecular masses of 7.4 kDa. The proteins differ only in residue 32, which is the position of their single aromatic side chain. Structural characterization reveals that the proteins fold in water solution into thermodynamically stable, alpha-helical conformations with well-defined tertiary structures. The proteins are resistant to pH changes and remain stable through the physiological pH range. The aromatic residues are shown to be located within the protein interior and shielded from the bulk phase, as designed. Differential pulse voltammetry was used to examine the reduction potentials of the aromatic side chains in alpha(3)W(1) and alpha(3)Y(1) and compare them to the potentials of tryptophan and tyrosine when dissolved in water. The tryptophan and tyrosine potentials were raised considerably when moved from a solution environment to a well-ordered protein milieu. We propose that the increase in reduction potential of the aromatic residues buried within the protein, relative to the solution potentials, is due to a lack of an effective protonic contact between the aromatic residues and the bulk solution.     

De novo peptide sequencing via tandem mass spectrometry.

Peptide sequencing via tandem mass spectrometry (MS/MS) is one of the most powerful tools in proteomics for identifying proteins. Because complete genome sequences are accumulating rapidly, the recent trend in interpretation of MS/MS spectra has been database search. However, de novo MS/MS spectral interpretation remains an open problem typically involving manual interpretation by expert mass spectrometrists. We have developed a new algorithm, SHERENGA, for de novo interpretation that automatically learns fragment ion types and intensity thresholds from a collection of test spectra generated from any type of mass spectrometer. The test data are used to construct optimal path scoring in the graph representations of MS/MS spectra. A ranked list of high scoring paths corresponds to potential peptide sequences. SHERENGA is most useful for interpreting sequences of peptides resulting from unknown proteins and for validating the results of database search algorithms in fully automated, high-throughput peptide sequencing.