Ashleigh Murch

Telomeric fusion is a major cytogenetic aberration of giant cell tumors of bone

Giant cell tumor of bone (GCT) is regarded as a rare primary bone neoplasm derived from stromal cells, which have the ability to recruit and harbor macrophage and multinucleated osteoclast-like giant cells. Despite being often considered benign, GCT is a problematic neoplasm in that it is aggressive, unpredictable and difficult to treat effectively. Cytogenetically GCT is characterised by a high frequency of telomeric fusion, a process which has been implicated in the production of chromosome instability and tumorigenesis. To extend our knowledge of the significance of telomere association in GCT, the cytogenetics of cell lines derived from spindle-shaped stromal-like mononuclear cells (the tumor cells) of GCT was investigated. Cell lines from three different patients showed telomeric association in all passages. The rate of telomeric association varied from line to line and from passage to passage, but there was no particular pattern to the variations. Many other cytogenetic abnormalities were seen as well as telomeric association, but these were rarely clonal. The nature of most of the other abnormalities seen, such as deleted chromosomes and chromosomes with additional unidentifiable material, was consistent with their being formed as a result of breakage of the dicentric fused chromosomes at a telophase. Chromosomes 13, 14 and 21 were most commonly involved in telomeric fusion. It appears that telomeric association persists in long-term cultures of GCT and is responsible for the accumulation of other associated cytogenetic aberrations. Telomeric reduction and telomerase activity may act as oncogenic events, promoting and sustaining the transformed GCT phenotype.

Socio-demographic disparities in the uptake of prenatal screening and diagnosis in Western Australia.

Introduction:  Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state‐wide programme.

First-trimester combined screening for Down syndrome and other fetal anomalies.

OBJECTIVE: This study assessed fetal outcomes for pregnancies identified at increased risk for Down syndrome by first-trimester combined ultrasound examination and maternal serum biochemistry screening. METHODS: First-trimester combined screening data were obtained from ultrasound clinics across Western Australia between August 2001 and October 2003. Prenatal screening data were linked with pregnancy outcome information held in state health database registers using probabilistic record-linkage techniques. RESULTS: In 50 of the 60 pregnancies affected by Down syndrome, the adjusted risk was greater than 1 in 300, providing a detection rate of 83% (95% confidence interval [CI] 74–93%). Among all women screened (n = 22,280), 827 had increased risk results but did not have a Down syndrome pregnancy, representing a false-positive rate of 3.7% (95% CI 3.5–3.9%). Ten cases of Down syndrome were detected among women considered not at increased risk, consistent with a false-negative rate of 1 in 2,227. First-trimester combined screening reduced the number of Down syndrome births by 50 in 22,280 (2.24 cases per 1,000 births), which represents the detection of one case of fetal Down syndrome for every 446 women screened. Furthermore, 25% of pregnancies with other birth defects occurred among those identified at increased risk of Down syndrome, and 1 in 8 pregnancies at increased risk were found to have a significant chromosomal or structural defect. CONCLUSION: First-trimester combined screening in Western Australia detected 83% (95% CI 74–93%) of Down syndrome pregnancies at a 3.7% (95% CI 3.5–3.9%) false-positive rate. LEVEL OF EVIDENCE: II-2

Clear cell renal cell carcinoma with smooth muscle stroma

A recent publication described 5 unusual clear cell renal tumors with prominent smooth muscle stroma that were characterized only by immunostaining. We report 3 additional tumors composed of clear cell renal cell carcinoma intimately admixed with abundant smooth muscle stroma. Epithelial differentiation of the malignant clear cell components and smooth muscle differentiation of the benign spindle cell stroma was confirmed by the immunostaining profiles and by electron microscopy. Fluorescence in situ hybridization analysis of chromosome 3 showed loss of the entire chromosome in 2 cases and loss of 3p in the third case. We therefore interpret these tumors as unique low-grade variants of clear cell renal cell carcinoma that have induced a prolific metaplastic stromal reaction. Extensive tissue sampling and immunostaining are recommended to distinguish cases with an extensive smooth muscle component from morphologically similar but benign lesions including angiomyolipoma, leiomyoma, or mixed epithelial and stromal tumor of the kidney.

Prenatal screening for Down syndrome in Australia: Costs and benefits of current and novel screening strategies

To analyse the cost‐effectiveness and performance of noninvasive prenatal testing (NIPT) for high‐risk pregnancies following first‐trimester screening compared with current practice.

The Impact of Antenatal Screening for Down Syndrome in Western Australia: 1980–1994

Summary: Since the early 1970s, women in Western Australia have been screened for fetal Down syndrome risk on the basis of maternal age. Women 35 years of age or more at delivery, were offered fetal karyotyping with genetic diagnostic testing via amniocentesis or chorionic villus sampling. An increase in the prevalence of Down syndrome of 3.9% per year (95% confidence interval: 1.8‐6.0%) was observed between 1980 and 1994, almost all of which was accounted for by increased maternal age. In 1991, a maternal serum screening (MSS) programme for Down syndrome was first implemented in Western Australia and has since evolved with 6 separate laboratories providing Down risk assessment in 1994. The gradual introduction of MSS programmes had little discernible impact until 1994, when 38% of Down syndrome fetuses were ascertained as a result of increased‐risk MSS tests and the birth prevalence of Down syndrome decreased significantly. In this report, we review antenatal screening programmes and their impact on the birth prevalence of Down syndrome in Western Australia.

First trimester predictors of adverse pregnancy outcomes.

Aim: To identify first trimester indicators of adverse pregnancy outcomes.

Primary renal synovial sarcoma confirmed by cytogenetic analysis: a lesion distinct from sarcomatoid renal cell carcinoma.

Primary synovial sarcoma rarely originates in the renal parenchyma. When this occurs, origin of this unusual tumor type has been the subject of debate in the literature, with a suggestion that previously reported cases may be more correctly described as renal cell carcinoma with sarcomatoid dedifferentiation. Synovial sarcoma and sarcomatoid renal cell carcinoma may be indistinguishable on pure histologic and immunohistochemical grounds, but these tumors contain distinctly different sets of chromosomal abnormalities. Most previous cases of primary renal synovial sarcoma were confirmed by molecular biology techniques, which detected the SYT-SSX gene fusion transcript typical of this tumor, but no details of the other chromosomal anomalies have been published. We report a case of primary renal synovial sarcoma confirmed by standard cytogenetic analysis, showing the characteristic t(X; 18)(p11.2:q11.2) translocation and other chromosomal aberrations that are typical of synovial sarcoma as opposed to sarcomatoid renal cell carcinoma.

Evaluation of fluorescence in-situ hybridization in monomorphic endometrial stromal neoplasms and their histological mimics: A review of 49 cases

To perform a population‐based review of monomorphic endometrial stromal tumours and their histological mimics presenting over a 20‐year period, including an evaluation of fluorescence in‐situ hybridization (FISH) for the JAZF1 and YWHAE breakaparts.

Novel BRD4-NUT fusion isoforms increase the pathogenic complexity in NUT midline carcinoma.

Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)–NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the ‘standard’ NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4–NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4–NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current treatments.