Allelic losses in carcinoma in situ and testicular germ cell tumours of adolescents and adults: evidence suggestive of the linear progression model

Testicular germ cell tumours (TGCTs) may arise through a process of multi-step carcinogenesis, and loss of heterozygosity (LOH) at specific loci is likely to be an important early event, although this has not been studied in detail. In order to explore the pathogenetic relationships among TGCTs, we investigated the genetic changes in testicular tumours that exhibit a disease continuum through the precursor carcinoma in situ (CIS) to either seminoma (SE) and/or non-seminomatous germ cell tumour (NSGCT). Universal amplification has been performed on 87 TGCT specimens and 36 samples of CIS cells microdissected from single paraffin-embedded tumour sections from 40 patients, including multiple specimens of CIS and TGCT cells of varied histology microdissected from 24 individual patients. Seventy-seven microsatellite markers were used to assay these samples for LOH at candidate regions selected from the literature, mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p and 18q. Construction of deletion maps for each of these regions identified common sites of deletion at 3q27–q28, 5q31, 5q34–q35, 9p22–p21 and 12q22, which correlate with allelic losses we have also observed in the precursor CIS cells. Evidence for allelic loss at 3q27–q28 was observed in all of the embryonal carcinoma samples analysed. We conclude that inactivation of gene(s) within these regions are likely to be early events in the development and progression of TGCTs. These results also provide molecular evidence in support of the hypothesis that SE is an intermediate stage of development within a single neoplastic pathway of progression from CIS precursor cells to NSGCT. © 2000 Cancer Research Campaig

Monodromy of Cyclic Coverings of the Projective Line

We show that the image of the pure braid group under the monodromy action on the homology of a cyclic covering of degree d of the projective line is an arithmetic group provided the number of branch points is sufficiently large compared to the degree.Comment: 47 pages (to appear in Inventiones Mathematicae

Specific detection of OCT3/4 isoform A/B/B1 expression in solid (germ cell) tumours and cell lines: Confirmation of OCT3/4 specificity for germ cell tumours

Background: OCT3/4 (POU5F1) is an established diagnostic immunohistochemical marker for specific histological variants of human malignant germ cell tumours (GCTs), including the seminomatous types and the stem cell component of non-seminomas, known as embryonal carcinoma. OCT3/4 is crucial for the regulation of pluripotency and the self-renewal of normal embryonic stem-and germ cells. Detection of expression of this transcription factor is complicated by the existence of multiple pseudogenes and isoforms. Various claims have been made about OCT3/4 expression in non-GCTs, possibly related to using nonspecific detection methods. False-positive findings undermine the applicability of OCT3/4 as a specific diagnostic tool in a clinical setting. In addition, false-positive findings could result in misinterpretation of pluripotency regulation in solid somatic cancers and their stem cells. Of the three identified isoforms-OCT4A, OCT4B and OCT4B1-only OCT4A proved to regulate pluripotency. Up until now, no convincing nuclear OCT4A protein expression has been shown in somatic cancers or tissues. Methods: This study investigates expression of the various OCT3/4 isoforms in GCTs (both differentiated and undifferentiated) and somatic (non-germ cell) cancers, including representative cell lines and xenografts. Results: Using specific methods, OCT4A and OCT4B1 are shown to be preferentially expressed in undifferentiated GCTs. The OCT4B variant shows no difference in expression between GCTs (either differentiated or undifferentiated) and somatic cancers. In spite of the presence of OCT4A mRNA in somatic cancer-derived cell lines, no OCT3/4

Triangulated Surfaces in Twistor Space: A Kinematical Set up for Open/Closed String Duality

We exploit the properties of the three-dimensional hyperbolic space to discuss a simplicial setting for open/closed string duality based on (random) Regge triangulations decorated with null twistorial fields. We explicitly show that the twistorial N-points function, describing Dirichlet correlations over the moduli space of open N-bordered genus g surfaces, is naturally mapped into the Witten-Kontsevich intersection theory over the moduli space of N-pointed closed Riemann surfaces of the same genus. We also discuss various aspects of the geometrical setting which connects this model to PSL(2,C) Chern-Simons theory.Comment: 35 pages, references added, slightly revised introductio