ORCID Profile
0000-0002-9959-7024
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512712
Abstract: ORF overexpression screen enrichment analysis
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NBT.3674
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2022
DOI: 10.1200/JCO.21.02108
Abstract: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66% 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512715
Abstract: ORF overexpression screen data
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2012
DOI: 10.1158/0008-5472.CAN-12-0203
Abstract: High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from in idual patients were analyzed along with 22 paired pretreatment and posttreatment s les. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res 72(16) 4060–73. ©2012 AACR.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S42003-019-0741-7
Abstract: Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1 , but not MALAT1 . Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6540319
Abstract: Abstract High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including i BCL2L1 /i (BCL-XL) and i BCL2L2 /i (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of i BCL2L1 /i decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of in idual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy. /
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41467-020-18151-Y
Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA s les, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological ergences between two reproducible somatic variant detection efforts.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13983-9
Abstract: Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2016
DOI: 10.1101/090134
Abstract: Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for 12 high grade serous ovarian carcinoma (HGSC) patients with pre- and post-chemotherapy s les collected in the Australian Ovarian Cancer Study. We additionally analyzed 16 patients from the cohort with post-treatment s les only, including five primary surgical s les exposed to neoadjuvant chemotherapy. Our approach integrates tumor whole genome and RNA sequencing with class I MHC binding prediction and mutational signatures of chemotherapy exposure extracted from two preclinical studies. The mutational signatures for cisplatin and cyclophosphamide identified in a preclinical model had significant but inexact associations with the relevant exposure in the clinical s les. In an analysis stratified by tissue type (solid tumor or ascites), relapse s les collected after chemotherapy harbored a median of 90% more expressed neoantigens than untreated primary s les, a figure that combines the effects of chemotherapy and other mutagenic processes operative during relapse. Neoadjuvant-treated primary s les showed no detectable increase over untreated s les. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0–16) of the expressed neoantigen burden in relapse s les. In both treated and untreated s les, most neoantigens were attributed to COSMIC Signature (3) , associated with BRCA disruption, Signature (1) , associated with a slow mutagenic process active in healthy tissue, and Signature (8) , of unknown etiology. Relapsed HGSC tumors harbor nearly double the predicted expressed neoantigen burden of primary s les, but mutations associated with chemotherapy signatures account for only a small part of this increase. The mutagenic processes responsible for most neoantigens are similar between primary and relapse s les. Our analyses are based on mutations detectable from whole genome sequencing of bulk s les and do not account for neoantigens present in small populations of cells.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2017
Abstract: Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Plasma and tumor s les were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma s les were available for most patients (24 of 30). Targeted licon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor s les from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
Publisher: MDPI AG
Date: 11-11-2021
Abstract: Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1–2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512694.V1
Abstract: Figure S1A. Cisplatin and paclitaxel sensitivity in ovarian cancer cell lines Figure S1B. Cell line growth curves in ORF screen Figure S1C. Candidate resistance genes scoring in {greater than or equal to}2 conditions in primary ORF screen Figure S2A. Expression of MDR1, encoded by ABCB1 Figure S2B. Overexpression of ABCB1 and paclitaxel response Figure S2C. Overexpression of ABCB1 and paclitaxel response in HGSOC cell lines Figure S2D. Effect of ABCB1 overexpression on cell growth with paclitaxel treatment Figure S2E. Effect of MDR1/P-glycoprotein inhibitor elacridar on paclitaxel response Figure S2F. Overexpression of ABCB1 and colony formation with paclitaxel treatment and effect of elacridar on colony formation Figure S3A. Cell line growth curves in mini-pool overexpression secondary screen Figure S3B. Mini-pool overexpression secondary screen Figure S3C. Top-ranked genes by LFC in mini-pool overexpression secondary screen Figure S4A. Cell line growth curves in CRISPR-Cas9 screen Figure S4B. CRISPR-Cas9 screen data from cisplatin+paclitaxel "low-dose" combination Figure S5A. Expression of BCL-XL and BCL-W Figure S5B. Overexpression of BCL2L1 (BCL-XL) or BCL2L2 (BCL-W) and paclitaxel response in HGSOC cell lines Figure S5C. Effect of overexpressing anti-apoptotic proteins on apoptotic priming Figure S5D. Expression of BCL-2 and MCL1 Figure S5E. Overexpression of BCL2 or MCL1 and apoptosis induction Figure S5F. Overexpression of BCL2 or MCL1 and paclitaxel or cisplatin response Figure S6. Cell cycle analysis of HGSOC cells overexpressing anti-apoptotic proteins Figure S7A. Genomic alterations in anti-apoptotic genes in primary ovarian cancer Figure S7B. Copy-number alterations of anti-apoptotic genes in primary HGSOC Figure S7C. Copy-number alterations of pro-apoptotic genes in primary HGSOC Figure S7D. Copy number and expression of anti-apoptotic genes in primary HGSOC Figure S7E. MCL1 and BCL2L1 are focally lified in HGSOC Figure S7F. Progression-free interval of patients with primary HGSOC with focal lifications of BCL2L1 or MCL1 Figure S8A. Copy number alterations of anti-apoptotic genes in ovarian cancer cell lines Figure S8B. Expression of anti-apoptotic genes in ovarian cancer cell lines Figure S9A. Expression of anti-apoptotic genes in platinum-sensitive and -resistant HGSOC Figure S9B. Expression of anti-apoptotic genes in paired platinum-sensitive and- resistant HGSOC Figure S10A. Effects of single-agent anti-apoptotic protein inhibitors on ovarian cancer cell lines Figure S10B. BH3 profiling of HGSOC cell lines with a panel of pro-apoptotic peptides
Publisher: Springer Science and Business Media LLC
Date: 27-02-2023
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6540319.V1
Abstract: Abstract High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including i BCL2L1 /i (BCL-XL) and i BCL2L2 /i (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of i BCL2L1 /i decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of in idual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy. /
Publisher: American Society of Hematology
Date: 20-10-2020
DOI: 10.1182/BLOODADVANCES.2020001576
Abstract: The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML s les to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
Publisher: Elsevier BV
Date: 03-2009
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14367-0
Abstract: The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53 , TLE4 , and TCF4 . We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and s les containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as s les with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512715.V1
Abstract: ORF overexpression screen data
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2224
Abstract: Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first ex le of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res 77(16) 4268–78. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512700
Abstract: CRISPR-Cas9 screen data
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13824-9
Abstract: Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , we dissect whole-genome sequencing data of over 2500 matched tumor-control s les from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX trunc ) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor s les contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX trunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13825-8
Abstract: In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor s les and 88% and 83% respectively on independent primary and metastatic s les, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512691.V1
Abstract: Supplementary detailed methods
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512709
Abstract: ORF constructs in secondary mini-pool overexpression screen
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512706
Abstract: Secondary mini-pool overexpression screen data
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512700.V1
Abstract: CRISPR-Cas9 screen data
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512706.V1
Abstract: Secondary mini-pool overexpression screen data
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512709.V1
Abstract: ORF constructs in secondary mini-pool overexpression screen
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512697.V1
Abstract: CRISPR-Cas9 screen enrichment analysis
Publisher: Springer Science and Business Media LLC
Date: 30-11-2020
DOI: 10.1038/S41467-020-20128-W
Abstract: Correction to this paper has been published: 0.1038/s41467-020-20128-w
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13929-1
Abstract: The discovery of driver mutations is one of the key motivations for cancer genome sequencing. Here , as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across multiple tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2583 cancer genomes from the PCAWG project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Working Group, DriverPower has the highest F1 score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-14052-X
Abstract: Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53 , MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1038/S41588-022-01230-9
Abstract: Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor s les, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-019-1907-7
Abstract: Cancer develops through a process of somatic evolution 1,2 . 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 3 . 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) 4 , 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 s les. A nearly fourfold ersification 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.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13885-W
Abstract: The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT , MDM2 , CDK4 , ERBB2 , CD274 , PDCD1LG2 , and IGF2 . TERT -associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non- lified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S41467-020-17359-2
Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2019
DOI: 10.1158/1541-7786.MCR-18-1243
Abstract: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2015
DOI: 10.1038/NATURE14410
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA s les from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 lification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in in idual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512691
Abstract: Supplementary detailed methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512712.V1
Abstract: ORF overexpression screen enrichment analysis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512697
Abstract: CRISPR-Cas9 screen enrichment analysis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22512694
Abstract: Figure S1A. Cisplatin and paclitaxel sensitivity in ovarian cancer cell lines Figure S1B. Cell line growth curves in ORF screen Figure S1C. Candidate resistance genes scoring in {greater than or equal to}2 conditions in primary ORF screen Figure S2A. Expression of MDR1, encoded by ABCB1 Figure S2B. Overexpression of ABCB1 and paclitaxel response Figure S2C. Overexpression of ABCB1 and paclitaxel response in HGSOC cell lines Figure S2D. Effect of ABCB1 overexpression on cell growth with paclitaxel treatment Figure S2E. Effect of MDR1/P-glycoprotein inhibitor elacridar on paclitaxel response Figure S2F. Overexpression of ABCB1 and colony formation with paclitaxel treatment and effect of elacridar on colony formation Figure S3A. Cell line growth curves in mini-pool overexpression secondary screen Figure S3B. Mini-pool overexpression secondary screen Figure S3C. Top-ranked genes by LFC in mini-pool overexpression secondary screen Figure S4A. Cell line growth curves in CRISPR-Cas9 screen Figure S4B. CRISPR-Cas9 screen data from cisplatin+paclitaxel "low-dose" combination Figure S5A. Expression of BCL-XL and BCL-W Figure S5B. Overexpression of BCL2L1 (BCL-XL) or BCL2L2 (BCL-W) and paclitaxel response in HGSOC cell lines Figure S5C. Effect of overexpressing anti-apoptotic proteins on apoptotic priming Figure S5D. Expression of BCL-2 and MCL1 Figure S5E. Overexpression of BCL2 or MCL1 and apoptosis induction Figure S5F. Overexpression of BCL2 or MCL1 and paclitaxel or cisplatin response Figure S6. Cell cycle analysis of HGSOC cells overexpressing anti-apoptotic proteins Figure S7A. Genomic alterations in anti-apoptotic genes in primary ovarian cancer Figure S7B. Copy-number alterations of anti-apoptotic genes in primary HGSOC Figure S7C. Copy-number alterations of pro-apoptotic genes in primary HGSOC Figure S7D. Copy number and expression of anti-apoptotic genes in primary HGSOC Figure S7E. MCL1 and BCL2L1 are focally lified in HGSOC Figure S7F. Progression-free interval of patients with primary HGSOC with focal lifications of BCL2L1 or MCL1 Figure S8A. Copy number alterations of anti-apoptotic genes in ovarian cancer cell lines Figure S8B. Expression of anti-apoptotic genes in ovarian cancer cell lines Figure S9A. Expression of anti-apoptotic genes in platinum-sensitive and -resistant HGSOC Figure S9B. Expression of anti-apoptotic genes in paired platinum-sensitive and- resistant HGSOC Figure S10A. Effects of single-agent anti-apoptotic protein inhibitors on ovarian cancer cell lines Figure S10B. BH3 profiling of HGSOC cell lines with a panel of pro-apoptotic peptides
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14351-8
Abstract: 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 s les, 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.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14352-7
Abstract: The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour s le. In simulations, we find TrackSig has a 3–5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.
No related grants have been discovered for Elizabeth Christie.