Publications by authors named "Nicola Waddell"

108 Publications

Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.

Genome Med 2022 05 30;14(1):58. Epub 2022 May 30.

Medical Genomics, Clinical Genomics and Genome Informatics Groups, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Background: Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials.

Methods: We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment.

Results: The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a 'hot' immune environment independent of the somatic mutations.

Conclusions: We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.
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http://dx.doi.org/10.1186/s13073-022-01060-8DOI Listing
May 2022

Anatomic position determines oncogenic specificity in melanoma.

Nature 2022 04 30;604(7905):354-361. Epub 2022 Mar 30.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Oncogenic alterations to DNA are not transforming in all cellular contexts. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.
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http://dx.doi.org/10.1038/s41586-022-04584-6DOI Listing
April 2022

Evaluation of a Genetics Education Program for Health Interpreters: A Pilot Study.

Front Genet 2021 3;12:771892. Epub 2022 Feb 3.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Health Interpreters enable effective communication between health practitioners and patients with limited knowledge of the predominant language. This study developed and evaluated a training session introducing Health Interpreters to genetics. The online training was delivered multiple times as a single 2-h session comprising lectures and activities. Participants completed questionnaires (pre-, post-, and 6-months follow-up) to assess the impact of training on knowledge, attitude, self-efficacy, and self-reported practice behaviour. Questionnaires were analysed using descriptive statistics, Fisher's Exact, or independent -test. In total, 118 interpreters participated in the training sessions. Respondent knowledge improved, with gains maintained at 6-months ( < 0.01). There were no changes in self-efficacy, and attitudes. Training did not change self-reported practice behaviour, but there was notable pre-existing variability in participants' methods of managing unknown genetic words. Most respondents agreed that training was useful (93%) and relevant (79%) to their work. More respondents reported learning more from the case study activity (86%) than the group activity (58%). Health Interpreters found the training acceptable and demonstrated sustained improvement in knowledge of genetic concepts. Increased delivery of this training and associated research is needed to assess findings in a larger cohort and to measure the impact on patients.
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http://dx.doi.org/10.3389/fgene.2021.771892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850313PMC
February 2022

Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis.

Cancer Res 2022 04;82(7):1208-1221

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

G9a and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, yet the precise roles that these enzymes play cooperatively in cancer is unclear. We demonstrate here that frequent concurrent upregulation of both G9a and EZH2 occurs in several human tumors. These methyltransferases cooperatively repressed molecular pathways responsible for tumor cell death. In genetically distinct tumor subtypes, concomitant inhibition of G9a and EZH2 potently induced tumor cell death, highlighting the existence of tumor cell survival dependency at the epigenetic level. G9a and EZH2 synergistically repressed expression of genes involved in the induction of endoplasmic reticulum (ER) stress and the production of reactive oxygen species. IL24 was essential for the induction of tumor cell death and was identified as a common target of G9a and EZH2. Loss of function of G9a and EZH2 activated the IL24-ER stress axis and increased apoptosis in cancer cells while not affecting normal cells. These results indicate that G9a and EZH2 promotes the evasion of ER stress-mediated apoptosis by repressing IL24 transcription, therefore suggesting that their inhibition may represent a potential therapeutic strategy for solid cancers.

Significance: These findings demonstrate a novel role for G9a and EZH2 histone methyltransferases in suppressing apoptosis, which can be targeted with small molecule inhibitors as a potential approach to improve solid cancer treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2218DOI Listing
April 2022

Re-analysis of genomic data: An overview of the mechanisms and complexities of clinical adoption.

Genet Med 2022 04 20;24(4):798-810. Epub 2022 Jan 20.

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

Re-analyzing genomic information from a patient suspected of having an underlying genetic condition can improve the diagnostic yield of sequencing tests, potentially providing significant benefits to the patient and to the health care system. Although a significant number of studies have shown the clinical potential of re-analysis, less work has been performed to characterize the mechanisms responsible for driving the increases in diagnostic yield. Complexities surrounding re-analysis have also emerged. The terminology itself represents a challenge because "re-analysis" can refer to a range of different concepts. Other challenges include the increased workload that re-analysis demands of curators, adequate reimbursement pathways for clinical and diagnostic services, and the development of systems to handle large volumes of data. Re-analysis also raises ethical implications for patients and families, most notably when re-classification of a variant alters diagnosis, treatment, and prognosis. This review highlights the possibilities and complexities associated with the re-analysis of existing clinical genomic data. We propose a terminology that builds on the foundation presented in a recent statement from the American College of Medical Genetics and Genomics and describes each re-analysis process. We identify mechanisms for increasing diagnostic yield and provide perspectives on the range of challenges that must be addressed by health care systems and individual patients.
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http://dx.doi.org/10.1016/j.gim.2021.12.011DOI Listing
April 2022

Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer.

Genome Med 2022 01 10;14(1). Epub 2022 Jan 10.

School of Biomedical Sciences, Queensland University of Technology located at the Translational Research Institute, Brisbane, QLD, Australia.

Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.

Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.

Results: PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.

Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.
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http://dx.doi.org/10.1186/s13073-021-00990-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751371PMC
January 2022

Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.

Cancer Cell 2022 01 23;40(1):88-102.e7. Epub 2021 Dec 23.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Mater Hospital, Sydney, NSW 2060, Australia. Electronic address:

We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2021.11.012DOI Listing
January 2022

Ask the people: developing guidelines for genomic research with Aboriginal and Torres Strait Islander peoples.

BMJ Glob Health 2021 11;6(11)

Aboriginal and Torres Strait Islander Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

In health and medical research, guidelines are a set of statements and recommendations, whereby experts or stakeholders assess published literature to generate practical advice for a specific audience. This emphasis on guidelines development with expert consultation and published literature is not practical or inclusive when working in disciplines with minimal data and addressing issues that concern under-represented communities. Here we describe the process used for developing guidelines for the conduct of genomic research projects in partnership with Aboriginal and Torres Strait Islander peoples. A new technology with individual and community level ethical and social implications, and First Nations peoples with cultural and community expectations for research. We developed the guidelines through a consultation process that used participatory action research to engage with various stakeholders during multiple rounds of tailored activities. The end product, 'Genomic Partnerships: Guidelines for Genomics Research with Aboriginal and Torres Strait Islander peoples of Queensland' reflects the needs of the end-users and perspectives of the Aboriginal and Torres Strait Islander peoples, communities and organisations that participated. Through this process, we have identified recommendations for developing guidelines with other under-represented communities.
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http://dx.doi.org/10.1136/bmjgh-2021-007259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572381PMC
November 2021

Precision diagnostics: integration of tissue pathology and genomics in cancer.

Pathology 2021 Dec 8;53(7):809-817. Epub 2021 Oct 8.

QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia; genomiQa, Brisbane, Qld, Australia.

Traditionally, cancer diagnosis and management has been reactionary in that symptoms lead to investigations, then a diagnosis is followed by clinical management. This process is heavily dependent on tissue diagnosis mainly by histopathology and to a lesser extent, cytopathology. However, in recent times there has been a shift towards precision medicine to enable prevention, prediction and personalisation in healthcare. The core of precision medicine is optimising therapeutic benefit for patients, by using genomic and molecular profiling, analogously termed precision pathology. This review explores (1) the evolution of pathology from a para-clinical discipline to a mainstream medical field integral to oncology tumour boards; (2) its critical role in preventative, diagnostic, therapeutic and follow-up cancer care; (3) the future of tissue pathology in the era of precision oncology; and (4) how pathologists may evolve to future-proof their profession.
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http://dx.doi.org/10.1016/j.pathol.2021.08.003DOI Listing
December 2021

Deep learning in cancer diagnosis, prognosis and treatment selection.

Genome Med 2021 09 27;13(1):152. Epub 2021 Sep 27.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, 4006, Australia.

Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.
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http://dx.doi.org/10.1186/s13073-021-00968-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477474PMC
September 2021

Correction: McCart Reed et al. The Genomic Landscape of Lobular Breast Cancer. 2021, , 1950.

Cancers (Basel) 2021 Aug 9;13(16). Epub 2021 Aug 9.

Centre for Clinical Research, The University of Queensland, Herston, Brisbane, QLD 4029, Australia.

The authors wish to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/cancers13164010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392523PMC
August 2021

Queensland Genomics: an adaptive approach for integrating genomics into a public healthcare system.

NPJ Genom Med 2021 Aug 18;6(1):71. Epub 2021 Aug 18.

Queensland Genomics, Queensland Health, Herston, QLD, Australia.

The establishment of genomics in health care systems has been occurring for the past decade. It is recognised that implementing genomics within a health service is challenging without a system-wide approach. Globally, as clinical genomics implementation programs have matured there is a growing body of information around program design and outcomes. Program structures vary depending on local ecosystems including the health system, politics and funding availability, however, lessons from other programs are important to the design of programs in different jurisdictions. Here we describe an adaptive approach to the implementation of genomics into a publicly funded health care system servicing a population of 5.1 million people. The adaptive approach enabled flexibility to facilitate substantial changes during the program in response to learnings and external factors. We report the benefits and challenges experienced by the program, particularly in relation to the engagement of people and services, and the design of both individual projects and the program as a whole.
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http://dx.doi.org/10.1038/s41525-021-00234-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373904PMC
August 2021

Acquired Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.

Cancer Res 2021 09 28;81(18):4709-4722. Epub 2021 Jul 28.

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. promoter methylation (me) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with gene silencing and homologous recombination deficiency (HRD). PDX models lost me following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.In a cohort of 12 patients with -methylated HGSC, various patterns of me were associated with genomic "scarring," indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain me after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous me and elevated gene expression (relative to homozygous me controls) after only neoadjuvant chemotherapy.As me loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. SIGNIFICANCE: Homozygous methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0774DOI Listing
September 2021

Evaluation of Crizotinib Treatment in a Patient With Unresectable GOPC-ROS1 Fusion Agminated Spitz Nevi.

JAMA Dermatol 2021 Jul;157(7):836-841

Peter MacCallum Cancer Centre, Melbourne, Australia.

Importance: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood.

Observations: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks.

Conclusions And Relevance: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.
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http://dx.doi.org/10.1001/jamadermatol.2021.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173474PMC
July 2021

Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication.

Cell Discov 2021 May 24;7(1):37. Epub 2021 May 24.

Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus-ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
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http://dx.doi.org/10.1038/s41421-021-00279-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143069PMC
May 2021

The Genomic Landscape of Lobular Breast Cancer.

Cancers (Basel) 2021 Apr 18;13(8). Epub 2021 Apr 18.

Centre for Clinical Research, The University of Queensland, Herston, Brisbane, QLD 4029, Australia.

Invasive lobular carcinoma (ILC) is the second most common breast cancer histologic subtype, accounting for approximately 15% of all breast cancers. It is only recently that its unique biology has been assessed in high resolution. Here, we present a meta-analysis of ILC sequencing datasets, to provide a long-awaited ILC-specific resource, and to confirm the prognostic value and strength of association between a number of clinico-pathology features and genomics in this special tumour type. We consider panel ( = 684), whole exome ( = 215) and whole genome sequencing data ( = 48), and review histology of The Cancer Genome Atlas cases to assign grades and determine whether the ILC is of classic type or a variant, such as pleomorphic, prior to performing statistical analyses. We demonstrate evidence of considerable genomic heterogeneity underlying a broadly homogeneous tumour type (typically grade 2, estrogen receptor (ER)-positive); with genomes exhibiting few somatic mutations or structural alterations, genomes with a hypermutator phenotype, and tumours with highly rearranged genomes. We show that while (E-cadherin) and mutations do not significantly impact survival, overall survival is significantly poorer for patients with a higher tumour mutation burden; this is also true for grade 3 tumours, and those carrying a somatic mutation (and these cases were more likely to be ER-negative). Taken together, we have compiled a meta-dataset of ILC with molecular profiling, and our analyses show that the genomic landscape significantly impacts the tumour's variable natural history and overall survival of ILC patients.
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http://dx.doi.org/10.3390/cancers13081950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073944PMC
April 2021

Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development.

Cancers (Basel) 2021 04 7;13(8). Epub 2021 Apr 7.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.

Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas ( = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set ( = 59,095). Ancestry-matched case-control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted , , , and as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (, , ) or base excision (, ) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases.
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http://dx.doi.org/10.3390/cancers13081762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067736PMC
April 2021

Radiomics Biomarkers Correlate with CD8 Expression and Predict Immune Signatures in Melanoma Patients.

Mol Cancer Res 2021 06 2;19(6):950-956. Epub 2021 Apr 2.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival ( = 0.00047 and = 0.0014, respectively) and worse overall survival ( = 0.0223 and = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with mutation status ( = 0.0389). RNA-sequencing indicated patients with immune "cold" signatures had worse survival, which was associated with CT biomarker, MPP4 ( = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers ( = 0.0028). IMPLICATIONS: CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/6/950/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-1038DOI Listing
June 2021

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations.

Toxins (Basel) 2021 02 14;13(2). Epub 2021 Feb 14.

Translational Venomics Group, Madrid Institute for Advanced Studies in Food, E28049 Madrid, Spain.

Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the -derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations.
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http://dx.doi.org/10.3390/toxins13020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918145PMC
February 2021

Histone Modifying Enzymes in Gynaecological Cancers.

Cancers (Basel) 2021 Feb 16;13(4). Epub 2021 Feb 16.

Medical Genomics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.
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http://dx.doi.org/10.3390/cancers13040816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919659PMC
February 2021

Developing a gene panel for pharmacoresistant epilepsy: a review of epilepsy pharmacogenetics.

Pharmacogenomics 2021 03 5;22(4):225-234. Epub 2021 Mar 5.

The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD, 4029, Australia.

Evaluating genes involved in the pharmacodynamics and pharmacokinetics of epilepsy drugs is critical to better understand pharmacoresistant epilepsy. We reviewed the pharmacogenetics literature on six antiseizure medicines (carbamazepine, perampanel, lamotrigine, levetiracetam, sodium valproate and zonisamide) and compared the genes found with those present on epilepsy gene panels using a functional annotation pathway analysis. Little overlap was found between the two gene lists; pharmacogenetic genes are mainly involved in detoxification processes, while epilepsy panel genes are involved in cell signaling and gene expression. Our work provides support for a specific pharmacoresistant epilepsy gene panel to assist antiseizure medicine selection, enabling personalized approaches to treatment. Future efforts will seek to include this panel in genomic analyses of pharmacoresistant patients, to determine clinical utility and patient treatment responses.
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http://dx.doi.org/10.2217/pgs-2020-0145DOI Listing
March 2021

Considerations for using population frequency data in germline variant interpretation: Cancer syndrome genes as a model.

Hum Mutat 2021 05 1;42(5):530-536. Epub 2021 Mar 1.

Genetics & Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Aggregate population genomics data from large cohorts are vital for assessing germline variant pathogenicity. However, there are no specifications on how sequencing quality metrics should be considered, and whether exome-derived and genome-derived allele frequencies should be considered in isolation. Germline genome sequence data were simulated for nine read-depths to identify a minimum acceptable read-depth for detecting variants. gnomAD exome-derived and genome-derived datasets were assessed for read-depth, for six key cancer genes selected for variant curation by ClinGen expert panels. Non-Finnish European allele frequency (AF) or filter AF of coding variants in these genes, assigned into frequency bins using modified ACMG-AMP criteria, was compared between exome-derived and genome-derived datasets. A 30X read-depth achieved acceptable precision and recall for detection of substitutions, but poor recall for small insertions/deletions. Exome-derived and genome-derived datasets exhibited low read-depth for different gene exons. Individual variants were mostly assigned to non-divergent AF bins (>95%) or filter AF bins (>97%). Two major bin divergences were resolved by applying the minimal acceptable read-depth threshold. These findings show the importance of assessing read-depth separately for population datasets sourced from different short-read sequencing technologies before assigning a frequency-based ACMG-AMP classification code for variant interpretation.
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http://dx.doi.org/10.1002/humu.24183DOI Listing
May 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Verifying explainability of a deep learning tissue classifier trained on RNA-seq data.

Sci Rep 2021 01 29;11(1):2641. Epub 2021 Jan 29.

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

For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within high-dimensional data is unclear. To test the reliability of the explainability model SHapley Additive exPlanations (SHAP), we developed a convolutional neural network to predict tissue classification from Genotype-Tissue Expression (GTEx) RNA-seq data representing 16,651 samples from 47 tissues. Our classifier achieved an average F1 score of 96.1% on held-out GTEx samples. Using SHAP values, we identified the 2423 most discriminatory genes, of which 98.6% were also identified by differential expression analysis across all tissues. The SHAP genes reflected expected biological processes involved in tissue differentiation and function. Moreover, SHAP genes clustered tissue types with superior performance when compared to all genes, genes detected by differential expression analysis, or random genes. We demonstrate the utility and reliability of SHAP to explain a deep learning model and highlight the strengths of applying ML to transcriptome data.
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http://dx.doi.org/10.1038/s41598-021-81773-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846764PMC
January 2021

CRISPR/Cas9-mediated genome editing of Schistosoma mansoni acetylcholinesterase.

FASEB J 2021 01;35(1):e21205

Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

CRISPR/Cas9-mediated genome editing shows cogent potential for the genetic modification of helminth parasites. We report successful gene knock-in (KI) into the genome of the egg of Schistosoma mansoni by combining CRISPR/Cas9 with single-stranded oligodeoxynucleotides (ssODNs). We edited the acetylcholinesterase (AChE) gene of S. mansoni targeting two guide RNAs (gRNAs), X5 and X7, located on exon 5 and exon 7 of Smp_154600, respectively. Eggs recovered from livers of experimentally infected mice were transfected by electroporation with a CRISPR/Cas9-vector encoding gRNA X5 or X7 combining with/ without a ssODN donor. Next generation sequencing analysis of reads of amplicon libraries spanning targeted regions revealed that the major modifications induced by CRISPR/Cas9 in the eggs were generated by homology directed repair (HDR). Furthermore, soluble egg antigen from AChE-edited eggs exhibited markedly reduced AChE activity, indicative that programed Cas9 cleavage mutated the AChE gene. Following injection of AChE-edited schistosome eggs into the tail veins of mice, an significantly enhanced Th2 response involving IL-4, -5, -10, and-13 was detected in lung cells and splenocytes in mice injected with X5-KI eggs in comparison to control mice injected with unmutated eggs. A Th2-predominant response, with increased levels of IL-4, -13, and GATA3, also was induced by X5 KI eggs in small intestine-draining mesenteric lymph node cells when the gene-edited eggs were introduced into the subserosa of the ileum of the mice. These findings confirmed the potential and the utility of CRISPR/Cas9-mediated genome editing for functional genomics in schistosomes.
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http://dx.doi.org/10.1096/fj.202001745RRDOI Listing
January 2021

Sharing genomic data from clinical testing with researchers: public survey of expectations of clinical genomic data management in Queensland, Australia.

BMC Med Ethics 2020 11 19;21(1):119. Epub 2020 Nov 19.

QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.

Background: There has been considerable investment and strategic planning to introduce genomic testing into Australia's public health system. As more patients' genomic data is being held by the public health system, there will be increased requests from researchers to access this data. It is important that public policy reflects public expectations for how genomic data that is generated from clinical tests is used. To inform public policy and discussions around genomic data sharing, we sought public opinions on using genomic data contained in medical records for research purposes in the Australian state of Queensland.

Methods: A total of 1494 participants completed an online questionnaire between February and May 2019. Participants were adults living in Australia. The questionnaire explored participant preferences for sharing genomic data or biological samples with researchers, and concerns about genomic data sharing.

Results: Most participants wanted to be given the choice to have their genomic data from medical records used in research. Their expectations on whether and how often they needed to be approached for permission on using their genomic data, depended on whether the data was identifiable or anonymous. Their willingness to sharing data for research purposes depended on the type of information being shared, what type of research would be undertaken and who would be doing the research. Participants were most concerned with genomics data sharing that could lead to discrimination (insurance and employment), data being used for marketing, data security, or commercial use.

Conclusions: Most participants were willing to share their genomic data from medical records with researchers, as long as permission for use was sought. However, the existing policies related to this process in Queensland do not reflect participant expectations for how this is achieved, particularly with anonymous genomics data. This inconsistency may be addressed by process changes, such as inclusion of research in addition to clinical consent or general research data consent programs.
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http://dx.doi.org/10.1186/s12910-020-00563-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678081PMC
November 2020

Queensland Consumers' Awareness and Understanding of Clinical Genetics Services.

Front Genet 2020 15;11:537743. Epub 2020 Oct 15.

Dermatology Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD, Australia.

As genetic testing becomes increasingly utilized in health care, consumer awareness and understanding is critical. Both are reported to be low in Australia, though there are limited studies to date. A consumer survey assessed perceived knowledge, awareness and attitudes toward genetic medicine, prior to consumers' genomics forums in Queensland in 2018 and 2019. Data was analyzed using -test and Mann-Whitney tests analysis to detect any associations between sociodemographic factors and familiarity or attitudes. This highly educated and experienced health consumer cohort reported they were significantly more familiar with the healthcare system generally than genetic medicine specifically ( < 0.0001). Consumers perceived that genetic testing would be significantly more important in the future than it is currently ( < 0.00001). Consumers agreed that genetic testing should be promoted (91.4%), made available (100%), better funded (94.2%), and offered to all pregnant women (81.6%). The preferred learning modality about genetics was internet sites (62.7%) followed by talks/presentations (30.8%). Benefits of genetic testing, reported in qualitative responses, included the potential for additional information to promote personal control and improve healthcare. Perceived concerns included ethical implications (including privacy and discrimination), and current limitations of science, knowledge and/or practice. This study demonstrates that even knowledgeable consumers have little familiarity with genetic medicine but are optimistic about its potential benefits. Ethical concerns, particularly concerns regarding genetic discrimination should inform legislation and policy. Consumers are supportive of online resources in increasing genomic literacy.
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http://dx.doi.org/10.3389/fgene.2020.537743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593610PMC
October 2020

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.

Sci Rep 2020 10 19;10(1):17687. Epub 2020 Oct 19.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7). Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).
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http://dx.doi.org/10.1038/s41598-020-74956-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572377PMC
October 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
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