Publications by authors named "Oliver Holmes"

51 Publications

Long-term outcomes of prostate radiotherapy for newly-diagnosed metastatic prostate cancer.

Prostate Cancer Prostatic Dis 2021 Apr 5. Epub 2021 Apr 5.

Radiation Medicine Program, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada.

Background: In patients presenting with metastatic prostate cancer, the role of local therapy is evolving. Two recently reported large-scale randomized trials suggest that radiotherapy (RT) directed at the prostate improves overall survival (OS) in patients with low metastatic burden. We reviewed the experience of prostate RT in this setting at our center.

Methods: The study population consisted of men with newly-diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) referred to a comprehensive cancer center between 2005 and 2015 and treated initially with androgen deprivation therapy. Patients were eligible for inclusion if they received (1) prostate RT with biological effective dose (BED) at least that of a course of 40 Gy in 15 fractions or (2) no prostate RT. The association between receipt of prostate RT and OS was studied. OS was estimated using the Kaplan-Meier method and Cox regression was used to identify factors associated with OS.

Results: The cohort consisted of 410 patients, of whom 128 received prostate RT. Median follow-up 61.0 months. On univariate analysis, receipt of prostate RT was associated with improved OS (HR 0.59, 95% CI 0.45-0.77, p = 0.0001). Median OS in those patients receiving prostate RT was 47.4 months versus 26.3 months in those not receiving prostate RT. In a multivariate Cox model, receipt of prostate RT remained associated with improved OS (HR 0.69, 95% CI 0.50-0.94, p = 0.02). In those treated with prostate RT, increasing BED was also associated with improved OS (HR 0.87 per 10 Gy increase, 95% CI 0.76-0.99, p = 0.03).

Conclusions: This cohort represents the largest single-center experience of primary tumor-directed RT in mHSPC reported to date. In this population, receipt of prostate RT was associated with improved OS and the magnitude of the OS benefit was clinically significant. The possibility of an RT dose-response gradient in this setting merits further study.
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http://dx.doi.org/10.1038/s41391-021-00339-yDOI Listing
April 2021

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas.

Oncologist 2021 Mar 9. Epub 2021 Mar 9.

Foundation Medicine, Inc., Morrisville, North Carolina, USA.

Introduction: Pembrolizumab was approved with an accompanying companion diagnostic (CDx) assay (PD-L1 DAKO 22C3) for urothelial carcinoma (UC). In this study, we further characterize the clinicopathologic and genomic features of UC that are programmed death-ligand 1 (PD-L1) positive.

Materials And Methods: The cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP). All PD-L1 IHC testing was performed using the DAKO 22C3 CDx assay for UC. PD-L1 positivity was determined at a combined positive score ≥ 10.

Results: A total of 44.5% (235/528) patients with UC were PD-L1 . A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) versus metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites. CGP revealed PD-L1 patients had more frequent genomic alterations (GAs) in TP53 (p = .006) and RB1 (p = .003) and less frequent GAs in FGFR3 (p = .001) and MTAP (p = .028). The APOBEC mutational signature and tumor mutational burden (TMB)-high were more common in PD-L1 patients. By testing patients with UC with CGP, in addition to PD-L1 IHC, an additional 97 patients (18.4%) in the total cohort were eligible for immunotherapy based on TMB status.

Conclusion: PD-L1 and PD-L1 urothelial carcinomas are genomically different. Also, our study provides the framework for future clinical investigation with regard to specimen site selection for PD-L1 testing as well as candidate biomarker genomic alterations that may predict for better response or lack of response to immune checkpoint inhibitors.

Implications For Practice: In this study, a higher prevalence of TP53 and RB1 alterations and APOBEC mutational signatures in the PD-L1 urothelial carcinoma disease subset and enrichment of FGFR3 alterations in the PD-L1 disease subset were found. These data provide the basis for future investigation into the role of these genomic changes as positive and negative predictors of immunotherapy response. Also, differences wer seen in PD-L1 positivity based on the collection site of the sample, which can provide a framework for future clinical trial design and could influence sample selection for PD-L1 testing in patients with urothelial carcinoma when multiple samples are available.
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http://dx.doi.org/10.1002/onco.13753DOI Listing
March 2021

First results of the EORTC-SPECTA/Arcagen study exploring the genomics of rare cancers in collaboration with the European reference network EURACAN.

ESMO Open 2020 12;5(6):e001075

Department of Medical Oncology, Center Léon Bérard, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France.

Purpose: Rare cancers are defined by an incidence of <6 out of 100 000 cases per year. They are under-represented in clinical research including tumour molecular analysis. The aim of Arcagen is to generate a multinational database integrating clinical and molecular information of patients with rare cancers.

Patients And Methods: We present the retrospective feasibility cohort of patients with rare cancers, with previously collected tumour samples available from any stage. Molecular analysis was performed using FoundationOne CDx for all histologies except for sarcoma where FoundationOne Heme was used. Clinical data including demographic data, medical history, malignant history, treatment and survival data were collected.

Results: Eighty-seven patients from three centres were screened; molecular data were obtained for 77 patients (41 sarcomas, 9 yolk sac tumours, 14 rare head and neck cancers, 13 thymomas). The median age at the time of diagnosis was 48 (range 28-85). Most patients had reportable genomic alterations (89%). The most common alterations were linked to cell cycle regulation (TP53, RB1, CDKN2A/B deletions and MDM2 amplification). Multiple activating single-nucleotide variants (SNVs) could be detected in the RAS/RAF family. The tumour mutational burden status was globally low across all samples with a median of 3 Muts/MB (range 0-52). Only 4 cases (ie, 4.7% of tumours) had direct actionable mutations for a treatment approved in Europe within the patient's tumour type.

Conclusion: The Arcagen project aims to bridge the gap and improve knowledge of the molecular landscape of rare cancers by prospectively recruiting up to 1000 patients.
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http://dx.doi.org/10.1136/esmoopen-2020-001075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709508PMC
December 2020

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

Nat Commun 2020 10 16;11(1):5259. Epub 2020 Oct 16.

Center for Rare Melanomas, University of Colorado Cancer Center, Aurora, Colorado, USA.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
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http://dx.doi.org/10.1038/s41467-020-18988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567804PMC
October 2020

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer.

Oncologist 2020 11 14;25(11):943-953. Epub 2020 Sep 14.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Background: We examined the current biomarker landscape in breast cancer when programmed death-ligand 1 (PD-L1) testing is integrated with comprehensive genomic profiling (CGP).

Material And Methods: We analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD-L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-; n = 159), HER2-positive (n = 32), and triple-negative breast cancer (TNBC) cohorts (n = 121).

Results: We found that in the TNBC cohort, 43% (52/121) were immunocyte PD-L1-positive, and in the HR+/HER2- cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab-paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy-associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD-L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD-L1 IHC.

Conclusion: Our integrated PD-L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options.

Implications For Practice: This integrated programmed death-ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration-approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor-positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple-negative breast cancer.
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http://dx.doi.org/10.1634/theoncologist.2020-0449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648336PMC
November 2020

Using whole-genome sequencing data to derive the homologous recombination deficiency scores.

NPJ Breast Cancer 2020 7;6:33. Epub 2020 Aug 7.

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD Australia.

The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particular or deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicative of response to certain therapeutic strategies. Studies have used whole-exome sequencing to derive the HRD score, however, with increasing use of whole-genome sequencing (WGS) to characterise tumour genomes, there has yet to be a comprehensive comparison between HRD scores derived by array versus WGS. Here we demonstrate that there is both a high correlation and a good agreement between array- and WGS-derived HRD scores and between the scores derived from WGS and downsampled WGS to represent shallow WGS. For samples with an HRD score close to threshold for stratifying HR proficiency or deficiency there was however some disagreement in the HR status between array and WGS data, highlighting the importance of not relying on a single method of ascertaining the homologous recombination status of a tumour.
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http://dx.doi.org/10.1038/s41523-020-0172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414867PMC
August 2020

Geometric inaccuracy and co-registration errors for CT, DynaCT and MRI images used in robotic stereotactic radiosurgery treatment planning.

Phys Med 2020 Jan 7;69:212-222. Epub 2020 Jan 7.

Department of Physics, Carleton University, Ottawa, Ontario, Canada; Department of Medical Physics, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Department of Radiology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Purpose: To measure the combined errors due to geometric inaccuracy and image co-registration on secondary images (dynamic CT angiography (dCTA), 3D DynaCT angiography (DynaCTA), and magnetic resonance images (MRI)) that are routinely used to aid in target delineation and planning for stereotactic radiosurgery (SRS).

Methods: Three phantoms (one commercial and two in-house built) and two different analysis approaches (commercial and MATLAB based) were used to quantify the magnitude of geometric image distortion and co-registration errors for different imaging modalities within CyberKnife's MultiPlan treatment planning software. For each phantom, the combined errors were reported as a mean target registration error (TRE). The mean TRE's for different intramodality imaging parameters (e.g., mAs, kVp, and phantom set-ups) and for dCTA, DynaCTA, and MRI systems were measured.

Results: Only X-ray based imaging can be performed with the commercial phantom, and the mean TRE ± standard deviation values were large compared to the in-house analysis using MATLAB. With the 3D printed phantom, even drastic changes in treatment planning CT imaging protocols did not greatly influence the mean TRE (<0.5 mm for a 1 mm slice thickness CT). For all imaging modalities, the largest mean TRE was found on DynaCT, followed by T2-weighted MR images (albeit all <1 mm).

Conclusions: The user may overestimate the mean TRE if the commercial phantom and MultiPlan were used solely. The 3D printed phantom design is a sensitive and suitable quality assurance tool for measuring 3D geometric inaccuracy and co-registration errors across all imaging modalities.
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http://dx.doi.org/10.1016/j.ejmp.2019.12.002DOI Listing
January 2020

Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.

Aust N Z J Psychiatry 2020 03 8;54(3):288-297. Epub 2019 Dec 8.

Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC, Australia.

Objective: Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response.

Methods: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia.

Results: An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group ( = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo ( = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury.

Conclusion: While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.
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http://dx.doi.org/10.1177/0004867419891246DOI Listing
March 2020

Dosimetric and radiobiological investigation of permanent implant prostate brachytherapy based on Monte Carlo calculations.

Brachytherapy 2019 Nov - Dec;18(6):875-882. Epub 2019 Aug 7.

Department of Physics, Carleton Laboratory for Radiotherapy Physics, Carleton University, Ottawa, Canada. Electronic address:

Purpose: Permanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort.

Methods And Materials: A cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose-volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated.

Results: For the target, D (V) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43.

Conclusions: DVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.
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http://dx.doi.org/10.1016/j.brachy.2019.06.008DOI Listing
April 2020

Running Genomic Analyses in the Cloud.

Stud Health Technol Inform 2019 Aug;266:149-155

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Genomic testing is rapidly moving into healthcare practice. However it comes with informatics challenges that the healthcare system has not previously faced - the raw data can be hundreds of gigabytes per test, the compute demands can be thousands of CPU hours, and the test can reveal deeply private health-srelated information that can have implications for anyone related to the person tested. While not a panacea, cloud computing has particular properties that can ameliorate some of these difficulties. This paper presents some of the key lessons learned while deploying a set of genomic analyses on cloud computing for Queensland Genomics.
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http://dx.doi.org/10.3233/SHTI190787DOI Listing
August 2019

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Nat Commun 2019 07 18;10(1):3163. Epub 2019 Jul 18.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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http://dx.doi.org/10.1038/s41467-019-11107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639323PMC
July 2019

Anemia is a poor prognostic factor for stage I non-small cell lung cancer (NSCLC) patients treated with Stereotactic Body Radiation Therapy (SBRT).

Clin Transl Radiat Oncol 2019 May 24;16:28-33. Epub 2019 Jan 24.

Division of Radiation Oncology, The University of Ottawa, Ottawa, ON, The Ottawa Hospital Cancer Centre, Canada.

•This study reports on the prognostic ability of haematological parameters for the largest known biopsy-proven stage-I medically inoperable cohort treated with SBRT.•After SBRT, the median values of Hb, ALC, ANC and TPC declined whereas the NLR and the PLR increased as compared to pre-SBRT.•Anemia along with other parameters was found to be a poor prognostic factor for local control despite treatment with SBRT to doses of >100 Gy BED.•Simple and minimally invasive methods like a peripheral blood sample can provide prognostic information even for stage-I NSCLC patients.•Patient, tumor and treatment factors along with molecular markers should be used to create risk stratification models that can guide therapy.
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http://dx.doi.org/10.1016/j.ctro.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423348PMC
May 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

Selective and super-selective C-arm based cone beam CT angiography (CBCTA) with DynaCT for CyberKnife radiosurgery planning of intracranial arteriovenous malformations (AVMs).

J Radiosurg SBRT 2018 ;5(4):305-313

Division of Radiation Oncology, University of Ottawa, Ottawa, ON, Canada.

Background: Successful radiosurgery for intracranial arteriovenous malformations (AVMs) requires accurate delineation of the nidus in 3D. Exact targeting and precise equipment is needed to achieve obliteration of the nidus while minimizing toxicity to the surrounding brain. In some micro-AVMs and poorly visible AVMs we have used cone beam CT angiography (CBCTA) with selective and super-selective angiography where a micro-catheter is advanced into the feeding arteries- to assist with nidus definition for CyberKnife radiosurgery planning.

Methods: Four patients who had AVMs inadequately visualized with MRI, MRA, CT, CTA, and dynamic CT angiography (dCTA) were identified for selective angiography (2 had super-selective angiography) for CyberKnife radiosurgery. The mean age at the time of treatment was 45 years (range: 22 - 71 years). All patients had suffered prior hemorrhage and were deemed inoperable. Super-selective angiography was done under general anesthesia to minimize motion artefact and the risk of arterial dissection. Angiography was performed using the biplane angiographic suite (ArtisQ; Siemens). Cone beam reconstructions were performed using DynaCT software. For each scan, volumetric data was acquired over 20 seconds in a single rotation of the C-arm mounted flat-panel detector cone-beam CT system. The data set was imported into the CyberKnife TPS and co-registered with the treatment planning CT, T2 MRI and Toshiba dCTA. Delineation of the AVM nidus was performed by the multi-disciplinary AVM team.

Results: There were no adverse events related to the angiography or radiosurgery treatment. CBCTA data sets created using DynaCT were accurately co-registered with the treatment planning scans in the CyberKnife treatment planning system (Multiplan). For all 4 patients, feeding arteries, draining veins and nidi were clearly visualized and used to develop radiosurgery plans. Mean nidus size was 0.45cc (range: 0.07 - 1.00cc).

Conclusions: For intracranial micro-AVMs and AVMs otherwise poorly visualized using DSA, MRA, CTA or dCTA, selective and super-selective CBCTA images (created using DynaCT) can be successfully imported into the CyberKnife TPS to assist in nidus delineation. Advancement of a micro-catheter into the feeding arteries to allow continuous contrast injection during volumetric scanning constitutes super-selective CBCTA. This technique provides superior visualization of micro-AVMs and should be utilized for radiosurgery planning of poorly visualized AVMs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255721PMC
January 2018

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications.

J Pathol 2019 02 20;247(2):214-227. Epub 2018 Dec 20.

Department of Histopathology, Sullivan Nicolaides Pathology, Bowen Hills, Australia.

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5184DOI Listing
February 2019

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility.

Int J Cancer 2019 03 21;144(5):1049-1060. Epub 2018 Nov 21.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.
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http://dx.doi.org/10.1002/ijc.31791DOI Listing
March 2019

Reducing errors in prostate tracking with an improved fiducial implantation protocol for CyberKnife based stereotactic body radiotherapy (SBRT).

J Radiosurg SBRT 2018 ;5(3):217-227

Division of Radiation Oncology, The University of Ottawa, Ottawa ON, Canada.

Purpose: Ultra-hypofractionated radiotherapy with SBRT is an established technique for treating localized prostate cancer. CyberKnife based SBRT requires implantation of fiducial markers for soft tissue target tracking by the orthogonal KV X-ray imaging system. The spatial distribution of fiducial markers must allow accurate calculation of a 3D transformation that describes the position of the prostate within the reference frame of the planning CT scan. Accuray provides a fiducial implantation guideline for tracking soft tissue lesions. Despite using the guideline we experienced an unacceptably high rate of rotational tracking failure due to problems with fiducial placement. We adapted the Accuray guideline to prostate SBRT for improved fiducial placement and more reliable target tracking.Methods and materials: 54 patients with prostate adenocarcinoma were treated with ultra-hypofractionated radiotherapy on CyberKnife. Patients had platinum fiducial markers implanted transrectally under ultrasound guidance by a Radiologist. For the first 26 patients, fiducial markers were positioned following the Accuray fiducial placement guidelines for soft tissue lesions (cohort 1). The initial rotational tracking error rate was unacceptably high (23%). On review, inappropriate fiducial placement was identified as the cause of error (especially insufficient spacing between seeds). In October 2016 we developed a seed placement protocol specifically for implanting fiducial markers within the prostate and a second cohort of patients was treated thereafter (cohort 2, 28 patients). The stipulations of the original guideline are maintained while the modified protocol requires that 4 fiducial markers be implanted in the postero-lateral peripheral zone in a single coronal plane.

Results: In cohort 1, patients had a median age of 64 years (50 - 74), PSA of 6.6mcg/L (1.1 - 14.7), and prostate volume of 56 cc (22 - 125), while in cohort 2 they had a mean age of 65 years (53 - 75), PSA of 6.2 mcg/L (1 - 12) and prostate volume of 47 cc (21 - 106). The fiducial markers were easily visualized and there were no cases of urosepsis related to fiducial implantation. In 6 of 26 patients (23%) from cohort 1, only translational mapping without accurate spatial rotations could be calculated. After adopting the prostate specific fiducial implantation protocol, rotational tracking error was eliminated. Accurate 6 degree tracking (accounting for translations and rotations) was achieved in all 28 patients from cohort 2. Using an in-house computer script we analyzed the dose distributions resulting from rotational misalignments of -10, -5, -3, 3, 5, and 10 degrees along all three rotational axes (pitch, roll and yaw). Rotational misalignments result in decreased minimum dose to the PTV and increased maximum dose to OARs.

Conclusion: Implementing a prostate specific fiducial placement protocol for SBRT significantly improved our ability to track prostate motion in 6 degrees 77% to 100% reliability. Failure to track rotations can potentially lead to underdosing and overdosing of portions of the prostate and OARs respectively.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018049PMC
January 2018

Telomere sequence content can be used to determine ALT activity in tumours.

Nucleic Acids Res 2018 06;46(10):4903-4918

Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.

The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.
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http://dx.doi.org/10.1093/nar/gky297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007693PMC
June 2018

Age-not Charlson Co-morbidity Index-predicts for mortality after stereotactic ablative radiotherapy for medically inoperable stage I non-small cell lung cancer.

Clin Transl Radiat Oncol 2017 Aug 2;5:37-41. Epub 2017 Aug 2.

Division of Radiation Oncology, The University of Ottawa, Ottawa, Ontario, Canada.

Purpose: In this single institution retrospective study of patients with stage I medically inoperable non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR) we attempt to model overall survival (OS) using initial prognostic variables with specific attention on the Charlson co-morbidity index (CCI).

Methods: Between 2008 and 2013, 335 patients with medically inoperable stage I NSCLC were treated with SABR or hypofractionated radiotherapy (50-60 Gy in at least 5 Gy or 4 Gy fractions respectively) at our institution. Medical comorbidities and Charlson scores were determined by individual chart review. Patients were stratified into 3 groups based on the CCI score (0-1, 2-3, 4-9) and again based on the age-adjusted Charlson Comorbidity score (aCCI). Cumulative survival for each stratum was determined using the Kaplan-Meier method. Non-significant and confounding variables were identified and discounted from survival modeling. 3 sex stratified Cox regression models were tested: (1) aCCI with age and comorbidity combined; (2) age and CCI; (3) age alone, comorbidity removed.

Results: The median survival was 4.4 years and the median follow up 4.7 years. The median CCI and aCCI scores were 2 and 5 respectively. Patients with aCCI 7-12 had an increased hazard of death on univariate analysis HR 2.45 (1.15-5.22 95%CI,  = 0.02) and -excluding age as a competing variable- on multivariate analysis HR 2.25 (1.04-4.84 95%CI,  = 0.04). Patients with CCI 4-9 had an increased hazard of death on univariate analysis HR 1.57(1.30-2.90) but not on multivariate analysis. On formalized testing - with either continuous or categorical variables- all three survival models yielded similar coefficients of effect.

Conclusion: We identify male gender, weight loss greater than 10% and age as independent prognostic factors for patients treated with medically inoperable NSCLC treated with SABR or hypofractionated radiotherapy. Based on our survival models, age alone can be used interchangeably with aCCI or CCI plus age with the same prognostic value. Age is more reliably recorded, less prone to error and therefore a more useful metric than Charlson score in this group of patients.
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http://dx.doi.org/10.1016/j.ctro.2017.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833901PMC
August 2017

Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing.

PLoS One 2018 10;13(1):e0190264. Epub 2018 Jan 10.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studies have primarily utilised the Illumina HiSeq platforms. In this study we performed whole genome sequencing of three malignant pleural mesothelioma and matched normal samples using a new platform, the BGISEQ-500, and compared the results obtained with Illumina HiSeq X Ten. Germline and somatic, single nucleotide variants and small insertions or deletions were independently identified from data aligned human genome reference. The BGISEQ-500 and HiSeq X Ten platforms showed high concordance for germline calls with genotypes from SNP arrays (>99%). The germline and somatic single nucleotide variants identified in both sequencing platforms were highly concordant (86% and 72% respectively). These results indicate the potential applicability of the BGISEQ-500 platform for the identification of somatic and germline single nucleotide variants by whole genome sequencing. The BGISEQ-500 datasets described here represent the first publicly-available cancer genome sequencing performed using this platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190264PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761881PMC
February 2018

Whole-genome landscapes of major melanoma subtypes.

Nature 2017 05 3;545(7653):175-180. Epub 2017 May 3.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
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http://dx.doi.org/10.1038/nature22071DOI Listing
May 2017

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.

Oncologist 2017 03 16;22(3):255-263. Epub 2017 Feb 16.

Foundation Medicine, Cambridge, Massachusetts, USA.

Background: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality.

Methods: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC).

Results: GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving , , , and were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in experienced clinical benefit from vandetanib treatment.

Conclusion: CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.
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http://dx.doi.org/10.1634/theoncologist.2016-0279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344643PMC
March 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

Oncology 2016 21;91(6):348-353. Epub 2016 Oct 21.

The University of Texas MD Anderson Cancer Center, Houston, Tex., USA.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.
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http://dx.doi.org/10.1159/000449204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130597PMC
January 2017

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

J Pathol 2015 Nov 19;237(3):363-78. Epub 2015 Aug 19.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
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http://dx.doi.org/10.1002/path.4583DOI Listing
November 2015