Publications by authors named "Geoff Macintyre"

36 Publications

Loss of in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

JCO Precis Oncol 2021 Jun 22;5. Epub 2021 Jun 22.

Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.

Purpose: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition.

Methods: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing.

Results: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for , a key regulator of EMT reprogramming.

Conclusion: We show that EMT characterizes acutely resistant prostate tumors and that deletion of , a key transcriptional regulator of EMT, correlates with clinical response.
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http://dx.doi.org/10.1200/PO.20.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238292PMC
June 2021

MSH2-deficient prostate tumours have a distinct immune response and clinical outcome compared to MSH2-deficient colorectal or endometrial cancer.

Prostate Cancer Prostatic Dis 2021 Jun 9. Epub 2021 Jun 9.

Departments of Surgery and Urology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes.

Methods And Results: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours.

Conclusions: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.
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http://dx.doi.org/10.1038/s41391-021-00379-4DOI Listing
June 2021

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Cell 2021 04 7;184(8):2239-2254.e39. Epub 2021 Apr 7.

Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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http://dx.doi.org/10.1016/j.cell.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054914PMC
April 2021

FrenchFISH: Poisson Models for Quantifying DNA Copy Number From Fluorescence In Situ Hybridization of Tissue Sections.

JCO Clin Cancer Inform 2021 02;5:176-186

Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.

Purpose: Chromosomal aberration and DNA copy number change are robust hallmarks of cancer. The gold standard for detecting copy number changes in tumor cells is fluorescence in situ hybridization (FISH) using locus-specific probes that are imaged as fluorescent spots. However, spot counting often does not perform well on solid tumor tissue sections due to partially represented or overlapping nuclei.

Materials And Methods: To overcome these challenges, we have developed a computational approach called FrenchFISH, which comprises a nuclear volume correction method coupled with two types of Poisson models: either a Poisson model for improved manual spot counting without the need for control probes or a homogeneous Poisson point process model for automated spot counting.

Results: We benchmarked the performance of FrenchFISH against previous approaches using a controlled simulation scenario and tested it experimentally in 12 ovarian carcinoma FFPE-tissue sections for copy number alterations at three loci (c-Myc, hTERC, and SE7). FrenchFISH outperformed standard spot counting with 74% of the automated counts having < 1 copy number difference from the manual counts and 17% having < 2 copy number differences, while taking less than one third of the time of manual counting.

Conclusion: FrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue by both speeding up and improving the accuracy of spot count estimates.
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http://dx.doi.org/10.1200/CCI.20.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140799PMC
February 2021

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Clin Cancer Res 2020 10 17;26(20):5411-5423. Epub 2020 Jun 17.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572656PMC
October 2020

Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.

Nat Genet 2020 06 1;52(6):582-593. Epub 2020 Jun 1.

Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
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http://dx.doi.org/10.1038/s41588-020-0630-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353209PMC
June 2020

Genomic landscape of platinum resistant and sensitive testicular cancers.

Nat Commun 2020 05 4;11(1):2189. Epub 2020 May 4.

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.
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http://dx.doi.org/10.1038/s41467-020-15768-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198558PMC
May 2020

The evolutionary history of 2,658 cancers.

Nature 2020 02 6;578(7793):122-128. Epub 2020 Feb 6.

University of Toronto, Toronto, Ontario, Canada.

Cancer develops through a process of somatic evolution. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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http://dx.doi.org/10.1038/s41586-019-1907-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054212PMC
February 2020

Inferring structural variant cancer cell fraction.

Nat Commun 2020 02 5;11(1):730. Epub 2020 Feb 5.

Department of Computing and Information Systems, University of Melbourne, Parkville, VIC, 3010, Australia.

We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone's performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity.
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http://dx.doi.org/10.1038/s41467-020-14351-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002525PMC
February 2020

Copy number signatures and mutational processes in ovarian carcinoma.

Nat Genet 2018 09 13;50(9):1262-1270. Epub 2018 Aug 13.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.
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http://dx.doi.org/10.1038/s41588-018-0179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130818PMC
September 2018

Periprostatic fat tissue transcriptome reveals a signature diagnostic for high-risk prostate cancer.

Endocr Relat Cancer 2018 05 28;25(5):569-581. Epub 2018 Mar 28.

Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia.

Evidence suggests that altered adipose tissue homeostasis may be an important contributor to the development and/or progression of prostate cancer. In this study, we investigated the adipose transcriptional profiles of low- and high-risk disease to determine both prognostic potential and possible biological drivers of aggressive disease. RNA was extracted from periprostatic adipose tissue from patients categorised as having prostate cancer with either a low or high risk of progression based on tumour characteristics at prostatectomy and profiled by RNA sequencing. The expression of selected genes was then quantified by qRT-PCR in a cross-validation cohort. In the first phase, a total of 677 differentially transcribed genes were identified, from which a subset of 14 genes was shortlisted. In the second phase, a 3 gene (, , ) signature was refined and evaluated using recursive feature selection and cross-validation, obtaining a promising discriminatory utility (area under curve 0.72) at predicting the presence of high-risk disease. Genes implicated in immune and/or inflammatory responses predominated. Periprostatic adipose tissue from patients with high-risk prostate cancer has a distinct transcriptional signature that may be useful for detecting its occult presence. Differential expression appears to be driven by a local immune/inflammatory reaction to more advanced tumours, than any specific adipose tissue-specific tumour-promoting mechanism. This signature is transferable into a clinically usable PCR-based assay, which in a cross-validation cohort shows diagnostic potential.
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http://dx.doi.org/10.1530/ERC-18-0058DOI Listing
May 2018

How Subclonal Modeling Is Changing the Metastatic Paradigm.

Clin Cancer Res 2017 Feb 18;23(3):630-635. Epub 2016 Nov 18.

Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Australia.

A concerted effort to sequence matched primary and metastatic tumors is vastly improving our ability to understand metastasis in humans. Compelling evidence has emerged that supports the existence of diverse and surprising metastatic patterns. Enhancing these efforts is a new class of algorithms that facilitate high-resolution subclonal modeling of metastatic spread. Here we summarize how subclonal models of metastasis are influencing the metastatic paradigm. Clin Cancer Res; 23(3); 630-5. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0234DOI Listing
February 2017

Comparing nodal versus bony metastatic spread using tumour phylogenies.

Sci Rep 2016 Sep 22;6:33918. Epub 2016 Sep 22.

Departments of Urology and Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville 3050 Victoria, Australia.

The role of lymph node metastases in distant prostate cancer dissemination and lethality is ill defined. Patients with metastases restricted to lymph nodes have a better prognosis than those with distant metastatic spread, suggesting the possibility of distinct aetiologies. To explore this, we traced patterns of cancer dissemination using tumour phylogenies inferred from genome-wide copy-number profiling of 48 samples across 3 patients with lymph node metastatic disease and 3 patients with osseous metastatic disease. Our results show that metastatic cells in regional lymph nodes originate from evolutionary advanced extraprostatic tumour cells rather than less advanced central tumour cell populations. In contrast, osseous metastases do not exhibit such a constrained developmental lineage, arising from either intra or extraprostatic tumour cell populations, at early and late stages in the evolution of the primary. Collectively, this comparison suggests that lymph node metastases may not be an intermediate developmental step for distant osseous metastases, but rather represent a distinct metastatic lineage.
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http://dx.doi.org/10.1038/srep33918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031992PMC
September 2016

Sequencing Structural Variants in Cancer for Precision Therapeutics.

Trends Genet 2016 09 29;32(9):530-542. Epub 2016 Jul 29.

Cancer Research UK Cambridge Institute, University of Cambridge, UK. Electronic address:

The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of 'actionable' structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing.
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http://dx.doi.org/10.1016/j.tig.2016.07.002DOI Listing
September 2016

Reduction in expression of the benign AR transcriptome is a hallmark of localised prostate cancer progression.

Oncotarget 2016 May;7(21):31384-92

Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.

Background: Despite the importance of androgen receptor (AR) signalling to prostate cancer development, little is known about how this signalling pathway changes with increasing grade and stage of the disease.

Objective: To explore changes in the normal AR transcriptome in localised prostate cancer, and its relation to adverse pathological features and disease recurrence.

Design: Publically accessible human prostate cancer expression arrays as well as RNA sequencing data from the prostate TCGA. Tumour associated PSA and PSAD were calculated for a large cohort of men (n=1108) undergoing prostatectomy.

Outcome Measurements And Statistical Analysis: We performed a meta-analysis of the expression of an androgen-regulated gene set across datasets using Oncomine. Differential expression of selected genes in the prostate TCGA database was probed using the edgeR Bioconductor package. Changes in tumour PSA density with stage and grade were assessed by Student's t-test, and its association with biochemical recurrence explored by Kaplan-Meier curves and Cox regression.

Results: Meta-analysis revealed a systematic decline in the expression of a previously identified benign prostate androgen-regulated gene set with increasing tumour grade, reaching significance in nine of 25 genes tested despite increasing AR expression. These results were confirmed in a large independent dataset from the TCGA. At the protein level, when serum PSA was corrected for tumour volume, significantly lower levels were observed with increasing tumour grade and stage, and predicted disease recurrence.

Conclusions: Lower PSA secretion-per-tumour-volume is associated with increasing grade and stage of prostate cancer, has prognostic relevance, and reflects a systematic perturbation of androgen signalling.
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http://dx.doi.org/10.18632/oncotarget.8915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058764PMC
May 2016

A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance.

Br J Cancer 2016 Feb 26;114(4):454-62. Epub 2016 Jan 26.

Department of Surgery, Division of Urology, Royal Melbourne Hospital, The University of Melbourne, Parkville, Melbourne, Victoria, Australia.

Background: The objective of this study was to determine whether microRNA (miRNA) profiling of urine could identify the presence of urothelial carcinoma of the bladder (UCB) and to compare its performance characteristics to that of cystoscopy.

Methods: In the discovery cohort we screened 81 patients, which included 21 benign controls, 30 non-recurrers and 30 patients with active cancer (recurrers), using a panel of 12 miRNAs. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. This was trained using a three-fold cross validation approach and performance was measured using the area under the receiver operator characteristic curve (AUC). The miRNA signature was validated in an independent cohort of a further 50 patients.

Results: The best predictor to distinguish patients with UCB from non-recurrers was achieved using a combination of six miRNAs (AUC=0.85). This validated in an independent cohort (AUC=0.74) and detected UCB with a high sensitivity (88%) and sufficient specificity (48%) with all significant cancers identified. The performance of the classifier was best in detecting clinically significant disease such as presence of T1 Stage disease (AUC=0.92) and high-volume disease (AUC=0.81). Cystoscopy rates in the validation cohort would have been reduced by 30%.

Conclusions: Urinary profiling using this panel of miRNAs shows promise for detection of tumour recurrence in the surveillance of UCB. Such a panel may be useful in reducing the morbidity and costs associated with cystoscopic surveillance, and now merits prospective evaluation.
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http://dx.doi.org/10.1038/bjc.2015.472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815774PMC
February 2016

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer.

Nat Commun 2015 Apr 1;6:6605. Epub 2015 Apr 1.

1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.
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http://dx.doi.org/10.1038/ncomms7605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396364PMC
April 2015

Associating disease-related genetic variants in intergenic regions to the genes they impact.

PeerJ 2014 23;2:e639. Epub 2014 Oct 23.

Department of Computing and Information Systems, The University of Melbourne, VIC, Australia.

We present a method to assist in interpretation of the functional impact of intergenic disease-associated SNPs that is not limited to search strategies proximal to the SNP. The method builds on two sources of external knowledge: the growing understanding of three-dimensional spatial relationships in the genome, and the substantial repository of information about relationships among genetic variants, genes, and diseases captured in the published biomedical literature. We integrate chromatin conformation capture data (HiC) with literature support to rank putative target genes of intergenic disease-associated SNPs. We demonstrate that this hybrid method outperforms a genomic distance baseline on a small test set of expression quantitative trait loci, as well as either method individually. In addition, we show the potential for this method to uncover relationships between intergenic SNPs and target genes across chromosomes. With more extensive chromatin conformation capture data becoming readily available, this method provides a way forward towards functional interpretation of SNPs in the context of the three dimensional structure of the genome in the nucleus.
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http://dx.doi.org/10.7717/peerj.639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217187PMC
November 2014

Establishing and managing a global student network.

PLoS Comput Biol 2014 Oct 30;10(10):e1003920. Epub 2014 Oct 30.

The Centre for Neural Engineering, University of Melbourne, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1371/journal.pcbi.1003920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214619PMC
October 2014

Paving the way towards a successful and fulfilling career in computational biology.

PLoS Comput Biol 2014 May 1;10(5):e1003593. Epub 2014 May 1.

Centre for Neural Engineering, The University of Melbourne, Carlton, Victoria, Australia; Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1371/journal.pcbi.1003593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006700PMC
May 2014

Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer.

Clin Cancer Res 2014 Nov 25;20(21):5547-57. Epub 2014 Apr 25.

Departments of Urology and Surgery, Royal Melbourne Hospital; Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia

Purpose: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression.

Experimental Design: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset.

Results: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway.

Conclusions: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-3483DOI Listing
November 2014

Socrates: identification of genomic rearrangements in tumour genomes by re-aligning soft clipped reads.

Bioinformatics 2014 04 2;30(8):1064-1072. Epub 2014 Jan 2.

Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Department of Medical Biology, University of Melbourne, Victoria 3010, Melanoma Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Department of Pathology, The University of Melbourne, Victoria 3010, NICTA Victoria Laboratory, The University of Melbourne, Victoria 3010, Department of Computing and Information Systems, University of Melbourne, Victoria 3010, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Department of Mathematics and Statistics, The University of Melbourne, Victoria 3010 and Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Department of Medical Biology, University of Melbourne, Victoria 3010, Melanoma Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Department of Pathology, The University of Melbourne, Victoria 3010, NICTA Victoria Laboratory, The University of Melbourne, Victoria 3010, Department of Computing and Information Systems, University of Melbourne, Victoria 3010, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Department of Mathematics and Statistics, The University of Melbourne, Victoria 3010 and Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Department of Medical Biology, University of Melbourne, Victoria 3010, Melanoma Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Department of Pathology, The University of Melbourne, Victoria 3010, NICTA Victoria Laboratory, The University of Melbourne, Victoria 3010, Department of Computing and Information Systems, University of Melbourne, Victoria 3010, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Department of Mathematics and Statistics, The University of Melbourne, Victoria 3010 and Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Department of Medical Biology, University of Melbourne, Victoria 3010, Melanoma Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Department of Pathology, The University of Melbourne, Victoria 3010, NICTA Victoria Laboratory, The University of Melbourne, Victoria 3010, Department of Computing and Information Systems, University of Melbourne, Victoria 3010, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Department of Mathematics and Statistics, The University of Melbourne, Victoria 3010 and Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.

Motivation: Methods for detecting somatic genome rearrangements in tumours using next-generation sequencing are vital in cancer genomics. Available algorithms use one or more sources of evidence, such as read depth, paired-end reads or split reads to predict structural variants. However, the problem remains challenging due to the significant computational burden and high false-positive or false-negative rates.

Results: In this article, we present Socrates (SOft Clip re-alignment To idEntify Structural variants), a highly efficient and effective method for detecting genomic rearrangements in tumours that uses only split-read data. Socrates has single-nucleotide resolution, identifies micro-homologies and untemplated sequence at break points, has high sensitivity and high specificity and takes advantage of parallelism for efficient use of resources. We demonstrate using simulated and real data that Socrates performs well compared with a number of existing structural variant detection tools.

Availability And Implementation: Socrates is released as open source and available from http://bioinf.wehi.edu.au/socrates CONTACT: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btt767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982158PMC
April 2014

Curated microRNAs in urine and blood fail to validate as predictive biomarkers for high-risk prostate cancer.

PLoS One 2014 4;9(4):e91729. Epub 2014 Apr 4.

Division of Urology, Department of Surgery, Royal Melbourne Hospital and the University of Melbourne, Parkville, Victoria, Australia; Australian Prostate Cancer Research Epworth, Richmond, Victoria, Australia.

Purpose: The purpose of this study was to determine if microRNA profiling of urine and plasma at radical prostatectomy can distinguish potentially lethal from indolent prostate cancer.

Materials And Methods: A panel of microRNAs was profiled in the plasma of 70 patients and the urine of 33 patients collected prior to radical prostatectomy. Expression of microRNAs was correlated to the clinical endpoints at a follow-up time of 3.9 years to identify microRNAs that may predict clinical response after radical prostatectomy. A machine learning approach was applied to test the predictive ability of all microRNAs profiled in urine, plasma, and a combination of both, and global performance assessed using the area under the receiver operator characteristic curve (AUC). Validation of urinary expression of miRNAs was performed on a further independent cohort of 36 patients.

Results: The best predictor in plasma using eight miRs yielded only moderate predictive performance (AUC = 0.62). The best predictor of high-risk disease was achieved using miR-16, miR-21 and miR-222 measured in urine (AUC = 0.75). This combination of three microRNAs in urine was a better predictor of high-risk disease than any individual microRNA. Using a different methodology we found that this set of miRNAs was unable to predict high-volume, high-grade disease.

Conclusions: Our initial findings suggested that plasma and urinary profiling of microRNAs at radical prostatectomy may allow prognostication of prostate cancer behaviour. However we found that the microRNA expression signature failed to validate in an independent cohort of patients using a different platform for PCR. This highlights the need for independent validation patient cohorts and suggests that urinary microRNA signatures at radical prostatectomy may not be a robust way to predict the course of clinical disease after definitive treatment for prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091729PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976264PMC
June 2015

Workshops: a great way to enhance and supplement a degree.

PLoS Comput Biol 2014 Feb 27;10(2):e1003497. Epub 2014 Feb 27.

NICTA Victoria Research Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Victoria, Australia ; Department of Computing and Information Systems, The University of Melbourne, Victoria, Australia.

As part of the International Society for Computational Biology Student Council (ISCB-SC), Regional Student Groups (RSGs) have helped organise workshops in the emerging fields of bioinformatics and computational biology. Workshops are a great way for students to gain hands-on experience and rapidly acquire knowledge in advanced research topics where curriculum-based education is yet to be developed. RSG workshops have improved dissemination of knowledge of the latest bioinformatics techniques and resources among student communities and young scientists, especially in developing nations. This article highlights some of the benefits and challenges encountered while running RSG workshops. Examples cover a variety of subjects, including introductory bioinformatics and advanced bioinformatics, as well as soft skills such as networking, career development, and socializing. The collective experience condensed in this article is a useful starting point for students wishing to organise their own tailor-made workshops.
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http://dx.doi.org/10.1371/journal.pcbi.1003497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937119PMC
February 2014

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array.

BMC Genomics 2014 Jan 22;15:51. Epub 2014 Jan 22.

NICTA Victoria Research Laboratory, Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.

Background: The Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues.

Results: We comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation.

Conclusions: Our method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.
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http://dx.doi.org/10.1186/1471-2164-15-51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943510PMC
January 2014

Breaking the ice and forging links: the importance of socializing in research.

PLoS Comput Biol 2013 21;9(11):e1003355. Epub 2013 Nov 21.

Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Netherlands Bioinformatics Centre, Nijmegen, The Netherlands.

When meeting someone for the first time-whether another PhD student, or the Founding Editor-in-chief of PLOS Computational Biology-nothing breaks the ice like eating pancakes or having drinks together. A social atmosphere provides a relaxed, informal environment where people can connect, share ideas, and form collaborations. Being able to build a network and thrive in a social environment is crucial to a successful scientific career. This article highlights the importance of bringing people together who speak the same scientific language in an informal setting. Using examples of events held by Regional Student Groups of the ISCB's Student Council, this article shows that socializing is much more than simply sharing a drink.
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http://dx.doi.org/10.1371/journal.pcbi.1003355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836699PMC
July 2014

Ten simple rules for starting a regional student group.

PLoS Comput Biol 2013 21;9(11):e1003340. Epub 2013 Nov 21.

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

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http://dx.doi.org/10.1371/journal.pcbi.1003340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836698PMC
July 2014

The young PI buzz: learning from the organizers of the Junior Principal Investigator Meeting at ISMB-ECCB 2013.

PLoS Comput Biol 2013 7;9(11):e1003350. Epub 2013 Nov 7.

Delft Bioinformatics Lab, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands.

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http://dx.doi.org/10.1371/journal.pcbi.1003350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820508PMC
July 2014

The regional student group program of the ISCB student council: stories from the road.

PLoS Comput Biol 2013 26;9(9):e1003241. Epub 2013 Sep 26.

NICTA Victoria Research Laboratory, University of Melbourne, Parkville, Victoria, Australia.

The International Society for Computational Biology (ISCB) Student Council was launched in 2004 to facilitate interaction between young scientists in the fields of bioinformatics and computational biology. Since then, the Student Council has successfully run events and programs to promote the development of the next generation of computational biologists. However, in its early years, the Student Council faced a major challenge, in that students from different geographical regions had different needs; no single activity or event could address the needs of all students. To overcome this challenge, the Student Council created the Regional Student Group (RSG) program. The program consists of locally organised and run student groups that address the specific needs of students in their region. These groups usually encompass a given country, and, via affiliation with the international Student Council, are provided with financial support, organisational support, and the ability to share information with other RSGs. In the last five years, RSGs have been created all over the world and organised activities that have helped develop dynamic bioinformatics student communities. In this article series, we present common themes emerging from RSG initiatives, explain their goals, and highlight the challenges and rewards through specific examples. This article, the first in the series, introduces the Student Council and provides a high-level overview of RSG activities. Our hope is that the article series will be a valuable source of information and inspiration for initiating similar activities in other regions and scientific communities.
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http://dx.doi.org/10.1371/journal.pcbi.1003241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784494PMC
April 2014

Percutaneous image-guided biopsy of prostate cancer metastases yields samples suitable for genomics and personalised oncology.

Clin Exp Metastasis 2014 Feb 2;31(2):159-67. Epub 2013 Oct 2.

Division of Urology, Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia,

Personalised oncology through mutational profiling of cancers requires the procurement of fresh frozen tumour samples for genomics applications. While primary cancers are often surgically excised and therefore yield such tissue, metastases in the setting of a known cancer diagnosis are not routinely sampled prior to systemic therapy. Our study aimed to determine the suitability of extracted nucleic acids for genomics applications using distant metastatic prostate cancer samples obtained via percutaneous or surgical biopsy. Patients with metastatic prostate cancer were recruited for image-guided biopsy of metastases. Patients undergoing surgical procedures for the complications of metastases were also recruited. Tissue samples were flash frozen and cryosectioned for histological examination. DNA and RNA were simultaneously extracted and genomic DNA hybridised onto SNP arrays for genome-wide copy number analysis. 37 samples of metastatic tissue from seven patients with prostate cancer were obtained. Five of these underwent image-guided biopsies whilst two had therapeutic surgical procedures performed. 22 biopsy samples were obtained across the image-guided biopsy patients with 80 % of samples being successfully processed for downstream analysis. Nucleic acid yield from these samples were satisfactory for genomics applications. Copy number analysis revealed a median estimated tumour purity of 53 % and all samples showed chromosomal abnormalities suggestive of malignancy. The procurement of osseous metastatic prostate cancer from live patients, including the use of image-guided biopsy, is safe and feasible. Sufficient tissue can be obtained in a manner such that extracted nucleic acids are suitable for genomics research.
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http://dx.doi.org/10.1007/s10585-013-9617-2DOI Listing
February 2014
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