Centre for Cancer Research - Research Publications

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    Methyl-CpG binding domain 4, DNA glycosylase (MBD4)-associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype
    Blombery, P ; Ryland, GL ; Fox, LC ; Stark, Z ; Wall, M ; Jarmolowicz, A ; Roesley, A ; Thompson, ER ; Grimmond, SM ; Panicker, S ; Kwok, F (WILEY, 2022-07)
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    Denosumab and invasive cervical root resorption: a case report
    Beaumont, S ; Angel, CM ; Dawson, S-J (WILEY, 2022-06)
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    Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment
    Zethoven, M ; Martelotto, L ; Pattison, A ; Bowen, B ; Balachander, S ; Flynn, A ; Rossello, FJ ; Hogg, A ; Miller, JA ; Frysak, Z ; Grimmond, S ; Fishbein, L ; Tischler, AS ; Gill, AJ ; Hicks, RJ ; Dahia, PLM ; Clifton-Bligh, R ; Pacak, K ; Tothill, RW (NATURE PORTFOLIO, 2022-10-21)
    Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.
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    Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care
    Cuppen, E ; Elemento, O ; Rosenquist, R ; Nikic, S ; IJzerman, M ; Zaleski, ID ; Frederix, G ; Levin, L-A ; Mullighan, CG ; Buettner, R ; Pugh, TJ ; Grimmond, S ; Caldas, C ; Andre, F ; Custers, I ; Campo, E ; van Snellenberg, H ; Schuh, A ; Nakagawa, H ; von Kalle, C ; Haferlach, T ; Froehling, S ; Jobanputra, V (LIPPINCOTT WILLIAMS & WILKINS, 2022)
    PURPOSE: The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transform diagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that is starting to replace the standard of care for oncology molecular testing in health care systems around the world; however, the implementation and widescale adoption of this best-in-class testing is lacking. METHODS: Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection and answer questions regarding utility in different cancer types, cost-effectiveness and affordability, and other practical considerations for WGTS implementation. RESULTS: We review the current studies implementing WGTS in health care systems and provide a synopsis of the clinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory, costs, reimbursement, and incidental findings aspects of this test. CONCLUSION: WGTS is an appropriate comprehensive clinical test for many tumor types and can replace multiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number of clinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave the way for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosis and treatment for patients with cancer.
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    Author Correction: Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.
    Carlevaro-Fita, J ; Lanzós, A ; Feuerbach, L ; Hong, C ; Mas-Ponte, D ; Pedersen, JS ; PCAWG Drivers and Functional Interpretation Group, ; Johnson, R ; PCAWG Consortium, (Springer Science and Business Media LLC, 2022-12-08)
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    Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia
    Kimura, S ; Montefiori, L ; Iacobucci, I ; Zhao, Y ; Gao, Q ; Paietta, EM ; Haferlach, C ; Laird, AD ; Mead, PE ; Gu, Z ; Stock, W ; Litzow, M ; Rowe, JM ; Luger, SM ; Hunger, SP ; Ryland, GL ; Schmidt, B ; Ekert, PG ; Oshlack, A ; Grimmond, SM ; Rehn, J ; Breen, J ; Yeung, D ; White, DL ; Aldoss, I ; Jabbour, EJ ; Pui, C-H ; Meggendorfer, M ; Walter, W ; Kern, W ; Haferlach, T ; Brady, S ; Zhang, J ; Roberts, KG ; Blombery, P ; Mullighan, CG (AMER SOC HEMATOLOGY, 2022-06-16)
    Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.
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    Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy
    Thijssen, R ; Tian, L ; Anderson, MA ; Flensburg, C ; Jarratt, A ; Garnham, AL ; Jabbari, JS ; Peng, H ; Lew, TE ; Teh, CE ; Gouil, Q ; Georgiou, A ; Tan, T ; Djajawi, TM ; Tam, CS ; Seymour, JF ; Blombery, P ; Gray, DHD ; Majewski, IJ ; Ritchie, ME ; Roberts, AW ; Huang, DCS (AMER SOC HEMATOLOGY, 2022-11-17)
    Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.
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    Alpelisib Monotherapy for PI3K-Altered Pretreated Advanced Breast Cancer A Phase II Study
    Savas, P ; Lo, LL ; Luen, SJ ; Blackley, EF ; Callahan, J ; Moodie, K ; van Geelen, CT ; Ko, Y-A ; Weng, C-F ; Wein, L ; Silva, MJ ; Bujak, AZ ; Yeung, MM ; Ftouni, S ; Hicks, RJ ; Francis, PA ; Lee, CK ; Dawson, S-J ; Loi, S (AMER ASSOC CANCER RESEARCH, 2022-09)
    UNLABELLED: There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007.
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    Clinical validation and implementation of droplet digital PCR for the detection of BRAF mutations from cell-free DNA
    Arnolda, R ; Howlett, K ; Chan, T ; Raleigh, J ; Hatzimihalis, A ; Bell, A ; Fellowes, A ; Sandhu, S ; Mcarthur, GA ; Fox, SB ; Dawson, S-J ; Hewitt, C ; Jones, K ; Wong, SQ (ELSEVIER, 2022-10)
    Droplet digital PCR (ddPCR) has been demonstrated in many research studies to be a sensitive method in the analysis of circulating tumour DNA (ctDNA) for identifying mutations and tracking disease. The transition of ddPCR into the diagnostic setting requires a number of critical steps including the assessment of accuracy and precision and ultimately implementation into clinical use. Here we present the clinical validation of ddPCR for the detection of BRAF mutations (V600E and V600K) from plasma. We describe the performance characteristics assessed including the limit of blank, limit of detection, ruggedness, accuracy, precision and the effect of the matrix. Overall, each assay could achieve a limit of detection of 0.5% variant allele fraction and was highly accurate, with 100% concordance of results obtained from routine diagnostic testing of formalin fixed tumour samples or reference controls (n=36 for BRAF V600E and n=30 for BRAF V600K). Inter-laboratory reproducibility across 12 plasma samples for each assay was also assessed and results were 100% concordant. Overall, we report the successful validation and translation of a ddPCR assay into clinical routine practice.
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    Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses
    Chan, KL ; Gomez, J ; Cardinez, C ; Kumari, N ; Sparbier, CE ; Lam, EYN ; Yeung, MM ; Garciaz, S ; Kuzich, JA ; Ong, DM ; Brown, FC ; Chan, Y-C ; Vassiliadis, D ; Wainwright, EN ; Motazedian, A ; Gillespie, A ; Fennell, KA ; Lai, J ; House, IG ; Macpherson, L ; Ang, C-S ; Dawson, S-J ; Beavis, PA ; Wei, AH ; Burr, ML ; Dawson, MA (CELL PRESS, 2022-10-10)
    There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.