Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary

Carcinomas of unknown primary (CUP) represent between 3 and 10% of malignancies. Treatment with nonspecific chemotherapy is commonly unhelpful and the median survival is between 3 and 6 months. Gene expression microarray (GEM) analysis has demonstrated that molecular signatures can aid in tumour classification and propose foster primaries. In this study, we demonstrate the clinical utility of a diagnostic gene expression profiling tool and discuss its potential implications for patient management strategies. Paraffin tumour samples from 21 cases of ‘true' CUP patients in whom standard investigation had failed to determine a primary site of malignancy were investigated using diagnostic gene profiling. The results were reviewed in the context of histology and clinical history. Classification of tumour origin using the GEM method confirmed the clinicians' suspicion in 16 out of 21 cases. There was a clinical/GEM inconsistency in 4 out of 21 patients and a pathological/GEM inconsistency in 1 patient. The improved diagnoses by the GEM method would have influenced the management in 12 out of 21 cases. Genomic profiling and cancer classification tools represent a promising analytical approach to assist with the management of CUP patients. We propose that GEM diagnosis be considered when the primary clinical algorithm has failed to provide a diagnosis

A first glimpse at the Galactic plane with the ASKAP: the SCORPIO field

In the broad context of the Australian Square Kilometer Array Pathfinder (ASKAP) early-science phase and preparation for the related surveys, we report the first radio observations towards the Galactic plane. The targeted field was chosen to encompass the entire SCORPIO survey, one of the several pathfinder projects for the Evolutionary Map of the Universe survey planned with the ASKAP. The observations were carried out in 2018 January at a central frequency of 912 MHz, with 15 operational antennas, and covered a total area of about 40 square degrees in three different pointings. The final image has a resolution of 24.1 × 21.1 arcsec2 and a median rms of 541 μJy beam−1⁠. We were able to extract 3545 candidate sources, 75 per cent of them point sources. For a preliminary validation, a comparison with the 843 MHz Molonglo Galactic Plane Survey is presented. Although the present observations were obtained with the ASKAP only partially deployed, its unique capability to map complex sources, such as those inhabiting the Galactic plane, at different angular scales, is highlighted. Within the SCORPIO field all the previously classified H II regions, Planetary Nebulae (PNe), and supernovae remnants (SNRs), previously known to be radio sources, were detected. We also report new radio detections from several H II regions previously classified as ‘candidates’ or ‘radio quiet’ and from half of all the PNe in the SCORPIO field with robust classification. Most notably, we find numerous unclassified, extended sources which constitute a promising sample of candidates H II regions and SNRs

Cancers of unknown primary origin: current perspectives and future therapeutic strategies

It is widely accepted that systemic neoplastic spread is a late event in tumour progression. However, sometimes, rapidly invasive cancers are diagnosed because of appearance of metastatic lesions in absence of a clearly detectable primary mass. This kind of disease is referred to as cancer of unknown primary (CUP) origin and accounts for 3-5% of all cancer diagnosis. There is poor consensus on the extent of diagnostic and pathologic evaluations required for these enigmatic cases which still lack effective treatment. Although technology to predict the primary tumour site of origin is improving rapidly, the key issue is concerning the biology which drives early occult metastatic spreading. This review provides the state of the art about clinical and therapeutic management of this malignant syndrome; main interest is addressed to the most recent improvements in CUP molecular biology and pathology, which will lead to successful tailored therapeutic options

MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome

Background: The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Methods: Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. Results: MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). Conclusions: MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.11 page(s

A taxonomy of epithelial human cancer and their metastases

<p>Abstract</p> <p>Background</p> <p>Microarray technology has allowed to molecularly characterize many different cancer sites. This technology has the potential to individualize therapy and to discover new drug targets. However, due to technological differences and issues in standardized sample collection no study has evaluated the molecular profile of epithelial human cancer in a large number of samples and tissues. Additionally, it has not yet been extensively investigated whether metastases resemble their tissue of origin or tissue of destination.</p> <p>Methods</p> <p>We studied the expression profiles of a series of 1566 primary and 178 metastases by unsupervised hierarchical clustering. The clustering profile was subsequently investigated and correlated with clinico-pathological data. Statistical enrichment of clinico-pathological annotations of groups of samples was investigated using Fisher exact test. Gene set enrichment analysis (GSEA) and DAVID functional enrichment analysis were used to investigate the molecular pathways. Kaplan-Meier survival analysis and log-rank tests were used to investigate prognostic significance of gene signatures.</p> <p>Results</p> <p>Large clusters corresponding to breast, gastrointestinal, ovarian and kidney primary tissues emerged from the data. Chromophobe renal cell carcinoma clustered together with follicular differentiated thyroid carcinoma, which supports recent morphological descriptions of thyroid follicular carcinoma-like tumors in the kidney and suggests that they represent a subtype of chromophobe carcinoma. We also found an expression signature identifying primary tumors of squamous cell histology in multiple tissues. Next, a subset of ovarian tumors enriched with endometrioid histology clustered together with endometrium tumors, confirming that they share their etiopathogenesis, which strongly differs from serous ovarian tumors. In addition, the clustering of colon and breast tumors correlated with clinico-pathological characteristics. Moreover, a signature was developed based on our unsupervised clustering of breast tumors and this was predictive for disease-specific survival in three independent studies. Next, the metastases from ovarian, breast, lung and vulva cluster with their tissue of origin while metastases from colon showed a bimodal distribution. A significant part clusters with tissue of origin while the remaining tumors cluster with the tissue of destination.</p> <p>Conclusion</p> <p>Our molecular taxonomy of epithelial human cancer indicates surprising correlations over tissues. This may have a significant impact on the classification of many cancer sites and may guide pathologists, both in research and daily practice. Moreover, these results based on unsupervised analysis yielded a signature predictive of clinical outcome in breast cancer. Additionally, we hypothesize that metastases from gastrointestinal origin either remember their tissue of origin or adapt to the tissue of destination. More specifically, colon metastases in the liver show strong evidence for such a bimodal tissue specific profile.</p

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus

The ASKAP-EMU Early Science Project: Radio Continuum Survey of the Small Magellanic Cloud

We present two new radio continuum images from the Australian Square Kilometre Array Pathfinder (ASKAP) survey in the direction of the Small Magellanic Cloud (SMC). These images are part of the Evolutionary Map of the Universe (EMU) Early Science Project (ESP) survey of the Small and Large Magellanic Clouds. The two new source lists produced from these images contain radio continuum sources observed at 960 MHz (4489 sources) and 1320 MHz (5954 sources) with a bandwidth of 192 MHz and beam sizes of 30.0”×30.0” and 16.3”×15.1”, respectively. The median Root Mean Squared (RMS) noise values are 186 μJy beam−1 (960 MHz) and 165 μJy beam−1 (1320 MHz). To create point source catalogues, we use these two source lists, together with the previously published Molonglo Observatory Synthesis Telescope (MOST) and the Australia Telescope Compact Array (ATCA) point source catalogues to estimate spectral indices for the whole population of radio point sources found in the survey region. Combining our ASKAP catalogues with these radio continuum surveys, we found 7736 point-like sources in common over an area of 30 deg2. In addition, we report the detection of two new, low surface brightness supernova remnant candidates in the SMC. The high sensitivity of the new ASKAP ESP survey also enabled us to detect the bright end of the SMC planetary nebula sample, with 22 out of 102 optically known planetary nebulae showing point-like radio continuum emission. Lastly, we present several morphologically interesting background radio galaxies

Radio continuum sources behind the Large Magellanic Cloud

We present a comprehensive multifrequency catalogue of radio sources behind the Large Magellanic Cloud (LMC) between 0.2 and 20 GHz, gathered from a combination of new and legacy radio continuum surveys. This catalogue covers an area of ∼144 deg2 at angular resolutions from 45 arcsec to ∼3 arcmin. We find 6434 discrete radio sources in total, of which 3789 are detected at two or more radio frequencies. We estimate the median spectral index (α; where Sv ∼ να) of α = −0.89 and mean of −0.88 ± 0.48 for 3636 sources detected exclusively at two frequencies (0.843 and 1.384 GHz) with similar resolution [full width at half-maximum (FWHM) ∼40–45 arcsec]. The large frequency range of the surveys makes it an effective tool to investigate Gigahertz Peak Spectrum (GPS), Compact Steep Spectrum (CSS), and Infrared Faint Radio Source (IFRS) populations within our sample. We find 10 GPS candidates with peak frequencies near 5 GHz, from which we estimate their linear size. 1866 sources from our catalogue are CSS candidates with α  &amp;lt; −0.8. We found six candidates for High Frequency Peaker (HFP) sources, whose radio fluxes peak above 5 GHz and no sources with unconstrained peaks and α  &amp;gt; 0.5. We found optical counterparts for 343 of the radio continuum sources, of which 128 have a redshift measurement. Finally, we investigate the population of 123 IFRSs found in this study