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1. In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer

Author

Sebastien Martinez, Shifei Wu, Michael Geuenich, Ahmad Malik, Ramona Weber, Tristan Woo, Amy Zhang, Gun Ho Jang, Dzana Dervovic, Khalid N. Al-Zahrani, Ricky Tsai, Nassima Fodil, Philippe Gros, Steven Gallinger, G. Gregory Neely, Faiyaz Notta, Ataman Sendoel, Kieran Campbell, Ulrich Elling, and Daniel Schramek

Subjects
Science
Abstract

Abstract Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.

Published
2024
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2. Relative Belief Inferences from Decision Theory

Author

Michael Evans and Gun Ho Jang

Subjects
Bayesian inference, evidential inference, statistical evidence, relative belief, loss functions, Bayesian-unbiasedness, Science, Astrophysics, QB460-466, Physics, QC1-999
Abstract

Relative belief inferences are shown to arise as Bayes rules or limiting Bayes rules. These inferences are invariant under reparameterizations and possess a number of optimal properties. In particular, relative belief inferences are based on a direct measure of statistical evidence.

Published
2024
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3. Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers

Author

Joan Miguel Romero, Emma Titmuss, Yifan Wang, James Vafiadis, Alain Pacis, Gun Ho Jang, Amy Zhang, Bryn Golesworthy, Tatiana Lenko, Laura M. Williamson, Barbara Grünwald, Grainne M. O’Kane, Steven J. M. Jones, Marco. A. Marra, Julie M. Wilson, Steven Gallinger, Janessa Laskin, and George Zogopoulos

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22–0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.

Published
2023
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4. Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC)

Author

Jannat Pervin, Mohammad Asad, Shaolong Cao, Gun Ho Jang, Nikta Feizi, Benjamin Haibe-Kains, Joanna M. Karasinska, Grainne M. O’Kane, Steven Gallinger, David F. Schaeffer, Daniel J. Renouf, George Zogopoulos, and Oliver F. Bathe

Subjects
pancreatic ductal adenocarcinoma, pancreatic cancer, metabolism, deconvolution, prognosis, Genetics, QH426-470
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful.Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene’s expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes.Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype.Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype.

Published
2023
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5. Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma

Author

James T. Topham, Erica S. Tsang, Joanna M. Karasinska, Andrew Metcalfe, Hassan Ali, Steve E. Kalloger, Veronika Csizmok, Laura M. Williamson, Emma Titmuss, Karina Nielsen, Gian Luca Negri, Sandra E. Spencer Miko, Gun Ho Jang, Robert E. Denroche, Hui-li Wong, Grainne M. O’Kane, Richard A. Moore, Andrew J. Mungall, Jonathan M. Loree, Faiyaz Notta, Julie M. Wilson, Oliver F. Bathe, Patricia A. Tang, Rachel Goodwin, Gregg B. Morin, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J. M. Jones, David F. Schaeffer, and Daniel J. Renouf

Subjects
Science
Abstract

KRAS wildtype metastatic pancreatic ductal adenocarcinoma (mPDAC) could represent a distinct molecular entity from other PDACs. Here, the authors analyse KRAS wildtype mPDAC tumours using genomics and transcriptomics and find molecular similarities with cholangiocarcinomas.

Published
2022
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6. Intra-Tumoral CD8+ T-Cell Infiltration and PD-L1 Positivity in Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

Author

Bryn Golesworthy, Yifan Wang, Amanda Tanti, Alain Pacis, Joan Miguel Romero, Adeline Cuggia, Celine Domecq, Guillaume Bourdel, Robert E. Denroche, Gun Ho Jang, Robert C. Grant, Ayelet Borgida, Barbara T. Grünwald, Anna Dodd, Julie M. Wilson, Guillaume Bourque, Grainne M. O’Kane, Sandra E. Fischer, Chelsea Maedler Kron, Pierre-Olivier Fiset, Atilla Omeroglu, William D. Foulkes, Steven Gallinger, Marie-Christine Guiot, Zu-Hua Gao, and George Zogopoulos

Subjects
pancreatic cancer, tumor microenvironment, T-cell inflammation, immunotherapy, PD-L1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p=1, whereas none of the HR/MMR-intact cases met this threshold (p

Published
2022
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7. Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy

Author

Sylvia S.W. Ng, Gun Ho Jang, Irwin J. Kurland, Yunping Qiu, Chandan Guha, and Laura A. Dawson

Subjects
Hepatocellular carcinoma, Stereotactic body radiotherapy, Metabolomics, Biomarkers, Medicine, Medicine (General), R5-920
Abstract

Background: Stereotactic body radiotherapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). This study sought to identify differentially expressed plasma metabolites in HCC patients at baseline and early during SBRT, and to explore if changes in these metabolites early during SBRT may serve as biomarkers for radiation-induced liver injury and/or tumour response. Methods: Forty-seven HCC patients were treated with SBRT on previously published prospective trials. Plasma samples were collected at baseline and after one to two fractions of SBRT, and analysed by GC/MS and LC/MS for untargeted and targeted metabolomics profiling, respectively. Findings: Sixty-nine metabolites at baseline and 62 metabolites after one to two fractions of SBRT were differentially expressed, and strongly separated the Child Pugh (CP) B from the CP A HCC patients. These metabolites are associated with oxidative stress and alterations in hepatic cellular metabolism. Differential upregulation of serine, alanine, taurine, and lipid metabolites early during SBRT from baseline was noted in the HCC patients who demonstrated the greatest increase in CP scores at three months post SBRT, suggesting that high protein and lipid turnover early during SBRT may portend increased clinical liver toxicity. Twenty annotated metabolites including fatty acids, glycerophospholipids, and acylcarnitines were differentially upregulated early during SBRT from baseline and separated patients with complete/partial response from those with stable disease at three months post SBRT. Interpretation: Dysregulation of amino acid and lipid metabolism detected early during SBRT are associated with subsequent clinical liver injury and tumour response in HCC.

Published
2020
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8. Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer.

Author

Deena M A Gendoo, Robert E Denroche, Amy Zhang, Nikolina Radulovich, Gun Ho Jang, Mathieu Lemire, Sandra Fischer, Dianne Chadwick, Ilinca M Lungu, Emin Ibrahimov, Ping-Jiang Cao, Lincoln D Stein, Julie M Wilson, John M S Bartlett, Ming-Sound Tsao, Neesha Dhani, David Hedley, Steven Gallinger, and Benjamin Haibe-Kains

Subjects
Biology (General), QH301-705.5
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.

Published
2019
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10. A powerful test of parent-of-origin effects for quantitative traits using haplotypes.

Author

Rui Feng, Yinghua Wu, Gun Ho Jang, Jose M Ordovas, and Donna Arnett

Subjects
Medicine, Science
Abstract

Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing parent-of-origin effects have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this study, we develop a powerful maximum likelihood test to evaluate the parent-of-origin effects of SNPs on quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate parent-of-origin effects is to recruit one parent and as many offspring as possible under practical constraints. As a demonstration, we applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to test the parent-of-origin effects of the SNPs within the PPARGC1A, MTP and FABP2 genes on diabetes-related phenotypes, and found that several SNPs in the MTP gene show parent-of-origin effects on insulin and glucose levels.

Published
2011
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11. The value of GATA6 immunohistochemistry and computer-assisted diagnosis to predict clinical outcome in advanced pancreatic cancer

Author

Kai Duan, Gun-Ho Jang, Robert C. Grant, Julie M. Wilson, Faiyaz Notta, Grainne M. O’Kane, Jennifer J. Knox, Steven Gallinger, and Sandra Fischer

Subjects
Medicine, Science
Abstract

Abstract Combination chemotherapy, either modified FOLFIRINOX (mFFX) or gemcitabine–nabpaclitaxel, are used in the treatment of most patients with advanced pancreatic ductal adenocarcinoma (PDAC), yet robust biomarkers of outcome are currently lacking to guide regimen selection. Here, we tested GATA6 immunohistochemistry (IHC) as a putative biomarker in advanced PDAC. GATA6 is a transcription factor in normal pancreas development. Two pathologists, blinded to clinical and molecular data, independently assessed GATA6 IHC in biopsy specimens of 130 patients with advanced PDAC, in 2 distinct phases (without and with computer assistance using the open source software QuPath). Low GATA6 IHC expression was associated with shorter overall survival [median OS 6.2 months for patients with GATA6 low tumors vs. 11.5 months for patients with GATA6 high tumors, HR 1.66 (95% CI 1.15–2.40), P = 0.007]. Progression appears to be higher in GATA6-low tumors compared to GATA6-high tumors in patients treated with mFFX (P = 0.024) but not in patients treated with gemcitabine regimens. GATA6 IHC expression was significantly associated with molecular subtypes (P = 0.0003). Digital assistance markedly improved interrater concordance (Cohen’s kappa scores of 0.32 vs. 0.95). Our results provide strong evidence that GATA6 IHC can be used as a single biomarker in the clinic to predict clinical outcome in advanced PDAC, warranting further investigation in prospective clinical trials. These results provide the basis for an improved classification of PDAC and future biomarker design using digital pathology workflow.

Published
2021
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12. RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Author

Amina Jbara, Kuan-Ting Lin, Chani Stossel, Zahava Siegfried, Haya Shqerat, Adi Amar-Schwartz, Ela Elyada, Maxim Mogilevsky, Maria Raitses-Gurevich, Jared L. Johnson, Tomer M. Yaron, Ofek Ovadia, Gun Ho Jang, Miri Danan-Gotthold, Lewis C. Cantley, Erez Y. Levanon, Steven Gallinger, Adrian R. Krainer, Talia Golan, and Rotem Karni

Subjects
Multidisciplinary
Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases1–3. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.

Published
2023

13. Systemic inflammatory prognostic scores in advanced pancreatic adenocarcinoma

Author

Lucy X. Ma, Yifan Wang, Osvaldo Espin-Garcia, Michael J. Allen, Gun Ho Jang, Amy Zhang, Anna Dodd, Stephanie Ramotar, Shawn Hutchinson, Mustapha Tehfe, Ravi Ramjeesingh, James Biagi, Julie M. Wilson, Faiyaz Notta, Sandra E. Fischer, George Zogopoulos, Steven Gallinger, Robert C. Grant, Rama Khokha, Nathan Chan, Barbara T. Grünwald, Jennifer J. Knox, and Grainne M. O’Kane

Subjects
Cancer Research, Oncology
Published
2023

14. A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Author

Kyaw L. Aung, Elaine McWhirter, Stephen Welch, Lisa Wang, Sophia Lovell, Lee-Anne Stayner, Saara Ali, Anne Malpage, Barbara Makepeace, Makilpriya Ramachandran, Gun Ho Jang, Steven Gallinger, Tong Zhang, Tracy L. Stockley, Sandra E. Fischer, Neesha Dhani, David Hedley, Jennifer J. Knox, Lillian L. Siu, Rachel Goodwin, and Philippe L. Bedard

Subjects
Oncology, Gastroenterology
Published
2022

15. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Author

Mónica P de Andrés, Richard J Jackson, Irene Felipe, Sladjana Zagorac, Christian Pilarsky, Anna Melissa Schlitter, Jaime Martinez de Villareal, Gun Ho Jang, Eithne Costello, Steve Gallinger, Paula Ghaneh, William Greenhalf, Thomas Knösel, Daniel H Palmer, Petra Ruemmele, Wilko Weichert, Markus Buechler, Thilo Hackert, John P Neoptolemos, Faiyaz Notta, Núria Malats, Paola Martinelli, and Francisco X Real

Subjects
Gastroenterology
Abstract

ObjectiveGATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome.GATA4is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy.DesignWe analysed PDAC transcriptomic data, stratifying cases according toGATA4andGATA6expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects ofGATA4knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.ResultsGATA4messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low forGATA4andGATA6. Reduced expression ofGATA4had a minor transcriptional impact but low expression ofGATA4enhanced the effects ofGATA6low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival.GATA4andGATA6expression significantly decreased in metastases and negatively correlated with basal markers.ConclusionsGATA4andGATA6cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

Published
2022

16. Clinically impactful metabolic subtypes of pancreatic ductal adenocarcinoma (PDAC).

Author

Pervin, Jannat, Asad, Mohammad, Shaolong Cao, Gun Ho Jang, Feizi, Nikta, Haibe-Kains, Benjamin, Karasinska, Joanna M., O'Kane, Grainne M., Gallinger, Steven, Schaeffer, David F., Renouf, Daniel J., Zogopoulos, George, and Bathe, Oliver F.

Subjects
PANCREATIC duct, MACHINE learning, ADENOCARCINOMA, SURVIVAL rate, CELL proliferation, TUMOR microenvironment
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype. [ABSTRACT FROM AUTHOR]

Published
2023
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17. Supplementary Figure S1 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

David A. Tuveson, Youngkyu Park, Steven Gallinger, Faiyaz Notta, Michael Wigler, Christopher R. Vakoc, Alexander Krasnitz, Jesse Gillis, Ralph H. Hruban, Laura D. Wood, Nicholas J. Roberts, Richard A. Burkhart, Chang-Il Hwang, Hervé Tiriac, Tim D.D. Somerville, Risa Karakida Kawaguchi, Gun Ho Jang, Jude Kendall, Siran Li, Pascal Belleau, Brinda Alagesan, Dennis Plenker, Giuseppina Caligiuri, Benno Traub, Astrid Deschênes, Lindsey A. Baker, and Koji Miyabayashi

Abstract

Comparison of IGO- and OGO-derived lesions

Published
2023

18. Supplementary table 1 and figures 1-4 from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Supplemental Table S1 lists clinical characteristics for the study cohort. Figure S1 depicts results of batch correction. Figures S2 and S3 show comparisons between ERV levels and tumor content. Figure S4 shows ERV levels across different biopsy sites.

Published
2023

19. Data from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

David A. Tuveson, Youngkyu Park, Steven Gallinger, Faiyaz Notta, Michael Wigler, Christopher R. Vakoc, Alexander Krasnitz, Jesse Gillis, Ralph H. Hruban, Laura D. Wood, Nicholas J. Roberts, Richard A. Burkhart, Chang-Il Hwang, Hervé Tiriac, Tim D.D. Somerville, Risa Karakida Kawaguchi, Gun Ho Jang, Jude Kendall, Siran Li, Pascal Belleau, Brinda Alagesan, Dennis Plenker, Giuseppina Caligiuri, Benno Traub, Astrid Deschênes, Lindsey A. Baker, and Koji Miyabayashi

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC.Significance:Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.See related commentary by Pickering and Morton, p. 1448.This article is highlighted in the In This Issue feature, p. 1426

Published
2023

20. Supplemental Figures from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

David A. Tuveson, Steven Gallinger, Alexander Krasnitz, Jennifer Knox, Richard Moffitt, Julie M. Wilson, Sandra E. Fischer, Benjamin Hubert, Christopher R. Vakoc, Ellen Li, Kenneth H. Yu, Christopher L. Wolfgang, Allyson Ocean, Craig Devoe, James M. Crawford, Edward Kim, Faiyaz Notta, Grainne M. O'Kane, Michael A. Hollingsworth, Jonathan R. Brody, Paul M. Grandgenett, Jonathan M. Buscaglia, Dominick J. DiMaio, Jean L. Grem, Phyllis A. Gimotty, Jordan M. Winter, James D. Sullivan, William Nealon, Divyesh V. Sejpal, Peter Allen, Juan Carlos Bucobo, Maoxin Wu, Joseph Kim, Aaron Sasson, Brian M. Wolpin, Andrew J. Aguirre, Elizabeth Thompson, Ralph H. Hruban, Laura D. Wood, Hans Clevers, Christine A. Iacobuzio-Donahue, Gokce Askan, Nicolas LeComte, Else Driehuis, Laura Martello, Cinthya Y. Lowder, Austin B. Goetz, Rashesh Sanghvi, Minita Shah, Nicolas Robine, Kanika Arora, Molly Johnson, Jasmine C. Huynh, Ammar A. Javed, Randze Lerie D. Palmaira, Joseph F. LaComb, Michelle Ma, Hardik Patel, C. Megan Young, Koji Miyabayashi, Gun-Ho Jang, Robert E. Denroche, Richard A. Burkhart, Fieke E. M. Froeling, Tim D. D. Somerville, Astrid Deschênes, Dennis Plenker, Dannielle D. Engle, Pascal Belleau, and Hervé Tiriac

Abstract

Supplemental Figures

Published
2023

21. Supplementary Video3 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

David A. Tuveson, Youngkyu Park, Steven Gallinger, Faiyaz Notta, Michael Wigler, Christopher R. Vakoc, Alexander Krasnitz, Jesse Gillis, Ralph H. Hruban, Laura D. Wood, Nicholas J. Roberts, Richard A. Burkhart, Chang-Il Hwang, Hervé Tiriac, Tim D.D. Somerville, Risa Karakida Kawaguchi, Gun Ho Jang, Jude Kendall, Siran Li, Pascal Belleau, Brinda Alagesan, Dennis Plenker, Giuseppina Caligiuri, Benno Traub, Astrid Deschênes, Lindsey A. Baker, and Koji Miyabayashi

Abstract

Confocal z-stack imaging of immunofluorescent (IF) images of mStrawberry-hT3 grafts 4 weeks after IGO transplantation

Published
2023

22. Table S3 from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

David A. Tuveson, Steven Gallinger, Alexander Krasnitz, Jennifer Knox, Richard Moffitt, Julie M. Wilson, Sandra E. Fischer, Benjamin Hubert, Christopher R. Vakoc, Ellen Li, Kenneth H. Yu, Christopher L. Wolfgang, Allyson Ocean, Craig Devoe, James M. Crawford, Edward Kim, Faiyaz Notta, Grainne M. O'Kane, Michael A. Hollingsworth, Jonathan R. Brody, Paul M. Grandgenett, Jonathan M. Buscaglia, Dominick J. DiMaio, Jean L. Grem, Phyllis A. Gimotty, Jordan M. Winter, James D. Sullivan, William Nealon, Divyesh V. Sejpal, Peter Allen, Juan Carlos Bucobo, Maoxin Wu, Joseph Kim, Aaron Sasson, Brian M. Wolpin, Andrew J. Aguirre, Elizabeth Thompson, Ralph H. Hruban, Laura D. Wood, Hans Clevers, Christine A. Iacobuzio-Donahue, Gokce Askan, Nicolas LeComte, Else Driehuis, Laura Martello, Cinthya Y. Lowder, Austin B. Goetz, Rashesh Sanghvi, Minita Shah, Nicolas Robine, Kanika Arora, Molly Johnson, Jasmine C. Huynh, Ammar A. Javed, Randze Lerie D. Palmaira, Joseph F. LaComb, Michelle Ma, Hardik Patel, C. Megan Young, Koji Miyabayashi, Gun-Ho Jang, Robert E. Denroche, Richard A. Burkhart, Fieke E. M. Froeling, Tim D. D. Somerville, Astrid Deschênes, Dennis Plenker, Dannielle D. Engle, Pascal Belleau, and Hervé Tiriac

Abstract

Table S3

Published
2023

23. Supplementary Table 3 from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Supplemental Table S3 lists gene sets significantly enriched among genes up-regulated in VMP samples.

Published
2023

24. Data from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

Published
2023

25. Supplementary Table 4 from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Supplemental Table S4 lists gene sets significantly enriched among genes down-regulated in VMP samples.

Published
2023

26. Supplementary Table S1-S4 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

David A. Tuveson, Youngkyu Park, Steven Gallinger, Faiyaz Notta, Michael Wigler, Christopher R. Vakoc, Alexander Krasnitz, Jesse Gillis, Ralph H. Hruban, Laura D. Wood, Nicholas J. Roberts, Richard A. Burkhart, Chang-Il Hwang, Hervé Tiriac, Tim D.D. Somerville, Risa Karakida Kawaguchi, Gun Ho Jang, Jude Kendall, Siran Li, Pascal Belleau, Brinda Alagesan, Dennis Plenker, Giuseppina Caligiuri, Benno Traub, Astrid Deschênes, Lindsey A. Baker, and Koji Miyabayashi

Abstract

Supplementary Table S1 Survival times of IGO and OGO mice Supplementary Table S2 Characteristics of patient-derived organoids, including KRAS, TP53, SMAD4, CDKN2A mutation status and patient stage Supplementary Table S3 Summary of Survival Data, including engraftment rate, mean survival, metastatic frequency Supplementary Table S4 Primers for quantitative PCR

Published
2023

27. Supplementary Method SM1 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

David A. Tuveson, Youngkyu Park, Steven Gallinger, Faiyaz Notta, Michael Wigler, Christopher R. Vakoc, Alexander Krasnitz, Jesse Gillis, Ralph H. Hruban, Laura D. Wood, Nicholas J. Roberts, Richard A. Burkhart, Chang-Il Hwang, Hervé Tiriac, Tim D.D. Somerville, Risa Karakida Kawaguchi, Gun Ho Jang, Jude Kendall, Siran Li, Pascal Belleau, Brinda Alagesan, Dennis Plenker, Giuseppina Caligiuri, Benno Traub, Astrid Deschênes, Lindsey A. Baker, and Koji Miyabayashi

Abstract

Method Used to Define the Thresholds for Fast- and Slow-Progressing IGO-Derived Tumors

Published
2023

28. Supplemental Table Legends from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

David A. Tuveson, Steven Gallinger, Alexander Krasnitz, Jennifer Knox, Richard Moffitt, Julie M. Wilson, Sandra E. Fischer, Benjamin Hubert, Christopher R. Vakoc, Ellen Li, Kenneth H. Yu, Christopher L. Wolfgang, Allyson Ocean, Craig Devoe, James M. Crawford, Edward Kim, Faiyaz Notta, Grainne M. O'Kane, Michael A. Hollingsworth, Jonathan R. Brody, Paul M. Grandgenett, Jonathan M. Buscaglia, Dominick J. DiMaio, Jean L. Grem, Phyllis A. Gimotty, Jordan M. Winter, James D. Sullivan, William Nealon, Divyesh V. Sejpal, Peter Allen, Juan Carlos Bucobo, Maoxin Wu, Joseph Kim, Aaron Sasson, Brian M. Wolpin, Andrew J. Aguirre, Elizabeth Thompson, Ralph H. Hruban, Laura D. Wood, Hans Clevers, Christine A. Iacobuzio-Donahue, Gokce Askan, Nicolas LeComte, Else Driehuis, Laura Martello, Cinthya Y. Lowder, Austin B. Goetz, Rashesh Sanghvi, Minita Shah, Nicolas Robine, Kanika Arora, Molly Johnson, Jasmine C. Huynh, Ammar A. Javed, Randze Lerie D. Palmaira, Joseph F. LaComb, Michelle Ma, Hardik Patel, C. Megan Young, Koji Miyabayashi, Gun-Ho Jang, Robert E. Denroche, Richard A. Burkhart, Fieke E. M. Froeling, Tim D. D. Somerville, Astrid Deschênes, Dennis Plenker, Dannielle D. Engle, Pascal Belleau, and Hervé Tiriac

Abstract

Supplemental Table Legends

Published
2023

29. Supplementary Table 5 from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Supplemental Table S5 lists EGA accession numbers for each sample included in the study.

Published
2023

30. Supplementary table 2 from Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types

Author

Daniel J. Renouf, David F. Schaeffer, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Dixie L. Mager, Jonathan M. Loree, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Andrew J. Mungall, Richard A. Moore, Hui-Li Wong, Steve E. Kalloger, Gun-Ho Jang, Robert E. Denroche, Shehara Mendis, Michael K.C. Lee, Luka Culibrk, Joanna M. Karasinska, Laura M. Williamson, Erin D. Pleasance, Emma Titmuss, and James T. Topham

Abstract

Supplemental Table S2 lists all genes differentially expressed in VMP samples.

Published
2023

31. Data from hENT1 Expression Predicts Response to Gemcitabine and Nab-Paclitaxel in Advanced Pancreatic Ductal Adenocarcinoma

Author

Grainne M. O'Kane, Jennifer J. Knox, Robert C. Grant, Steven Gallinger, Faiyaz Notta, George Zogopoulos, Sandra E. Fischer, Julie Wilson, Bernard Lam, James Biagi, Ravi Ramjeesingh, Mustapha Tehfe, Shawn Hutchinson, Stephanie Ramotar, Anna Dodd, Robert E. Denroche, Amy Zhang, Michael Allen, Deirdre Kelly, Yifan Wang, Gun Ho Jang, and Sheron Perera

Abstract

Purpose:Modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) remain standard first-line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC.Experimental Design:COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal χ2 statistic.Results:253 patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median overall survival (OS) was 10.0 months in hENT1high versus 7.9 months in hENT1low (P = 0.02). In patients receiving mFFX, there was no difference in overall response rate (ORR; 35% vs. 28%, P = 0.56) or median OS (10.6 vs. 10.5 months, P = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1high compared with hENT1low tumors (43% vs. 21%, P = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1high versus 6.7 months hENT1low (P < 0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction P = 0.002).Conclusions:In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP.

Published
2023

32. Figure S6 from Altered Gene Expression along the Glycolysis–Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer

Author

David F. Schaeffer, Daniel J. Renouf, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Steven Gallinger, Jennifer J. Knox, Faiyaz Notta, Andrew Metcalfe, Cassia Warren, Malcolm J. Moore, Andrew J. Mungall, Richard A. Moore, Grainne M. O'Kane, Michael K.C. Lee, Hui-Li Wong, Laura M. Williamson, Luka Culibrk, Robert E. Denroche, Gun Ho Jang, Steve E. Kalloger, James T. Topham, and Joanna M. Karasinska

Abstract

Heatmap showing median gene expression levels (z-score) of genes involved in various pathways related to cellular metabolism. For each gene, within each of the four metabolic subgroups, expression values were assessed for significant deviation from zero using Wilcoxon signed rank test (mu = 0).

Published
2023

33. Supplementary Figure 1 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 1 shows the results of the Disambiguate algorithm used to assign the PDAC xenograft RNAseq reads to individual species

Published
2023

34. Figure S3 from A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer

Author

Steven Gallinger, George Zogopoulos, Yifan Wang, Ashton Connor, Jennifer J. Knox, Julie M. Wilson, Grainne M. O'Kane, Susan J. Done, Pamela S. Ohashi, Faiyaz Notta, Tracy L. McGaha, Rama Khokha, Peter Bronsert, Foram Vyas, Dianne Chadwick, Sheng-Ben Liang, Sharon Dhaliwal, Niandong Li, Jing Xu, John M.S. Bartlett, Angela De Luca, Ilinca M. Lungu, Robert E. Denroche, Amy Zhang, Sandra E. Fischer, Mehdi Masoomian, Aaditeya Jhaveri, Prashant P. Bavi, Gun-Ho Jang, Barbara Grünwald, and Joan M. Romero

Abstract

Supplementary Figure 3: Association of chemokine expression with a T cell-inflamed phenotype was validated in a second independent PDAC patient cohort

Published
2023

35. Supplementary Figure 9 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 9 shows the Cox proportional hazards model, integrating Moffitt transcriptomic subtype, tumour ploidy, stage and age

Published
2023

36. Supplementary Materials from Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics

Author

David F. Schaeffer, Daniel J. Renouf, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Steven Gallinger, Jennifer J. Knox, Rachel Goodwin, Patricia A. Tang, Oliver Bathe, Julie M. Wilson, Jonathan M. Loree, Faiyaz Notta, Andrew J. Mungall, Richard A. Moore, Grainne M. O'Kane, Hui-li Wong, Steve E. Kalloger, Erica S. Tsang, Robert E. Denroche, Gun Ho Jang, Laura M. Williamson, Veronika Csizmok, Michael K.C. Lee, Joanna M. Karasinska, and James T. Topham

Abstract

Supplementary Figures S1-7

Published
2023

37. Table S1 from A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer

Author

Steven Gallinger, George Zogopoulos, Yifan Wang, Ashton Connor, Jennifer J. Knox, Julie M. Wilson, Grainne M. O'Kane, Susan J. Done, Pamela S. Ohashi, Faiyaz Notta, Tracy L. McGaha, Rama Khokha, Peter Bronsert, Foram Vyas, Dianne Chadwick, Sheng-Ben Liang, Sharon Dhaliwal, Niandong Li, Jing Xu, John M.S. Bartlett, Angela De Luca, Ilinca M. Lungu, Robert E. Denroche, Amy Zhang, Sandra E. Fischer, Mehdi Masoomian, Aaditeya Jhaveri, Prashant P. Bavi, Gun-Ho Jang, Barbara Grünwald, and Joan M. Romero

Abstract

Supplementary Table 1: Top 99 genes associating with CD8+ TIL counts in primary resected cases

Published
2023

38. Data from Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial

Author

Jennifer J. Knox, Steven Gallinger, Malcolm J. Moore, Julie M. Wilson, Faiyaz Notta, David Hedley, Neesha Dhani, Paul M. Krzyzanowski, Lee Timms, Jen Jen Yeh, Richard A. Moffitt, Ashton A. Connor, Spring Holter, Mathieu Lemire, Sangeet Ghai, John M.S. Bartlett, Ilinca M. Lungu, Danielle Pasternack, Faridah Mbabaali, Jessica K. Miller, Robert C. Grant, Shari Moura, Hamzeh Albaba, Grainne M. O'Kane, Amy Zhang, Dianne Chadwick, Sheng-Ben Liang, Bernadette Southwood, Sean Creighton, Anna Dodd, Gun-Ho Jang, Robert E. Denroche, Sandra E. Fischer, and Kyaw L. Aung

Abstract

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19–52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344–54. ©2017 AACR.

Published
2023

39. Supplementary Figure 5 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 5 shows the immunohistochemical analysis of apoptotic activity in xenografts treated with gemcitabine mono- and combination therapies

Published
2023

40. Supplementary Figure 7 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 7 shows the comparison of COSMIC SBS mutational signatures between untreated parent xenografts vs. xenografts treated with gemcitabine-cisplatin

Published
2023

41. Supplementary Figure 3 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 3 shows the histological analysis of the xenografts evaluated in the preclinical trial

Published
2023

42. Online Supplementary Materials from Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial

Author

Jennifer J. Knox, Steven Gallinger, Malcolm J. Moore, Julie M. Wilson, Faiyaz Notta, David Hedley, Neesha Dhani, Paul M. Krzyzanowski, Lee Timms, Jen Jen Yeh, Richard A. Moffitt, Ashton A. Connor, Spring Holter, Mathieu Lemire, Sangeet Ghai, John M.S. Bartlett, Ilinca M. Lungu, Danielle Pasternack, Faridah Mbabaali, Jessica K. Miller, Robert C. Grant, Shari Moura, Hamzeh Albaba, Grainne M. O'Kane, Amy Zhang, Dianne Chadwick, Sheng-Ben Liang, Bernadette Southwood, Sean Creighton, Anna Dodd, Gun-Ho Jang, Robert E. Denroche, Sandra E. Fischer, and Kyaw L. Aung

Abstract

Supplementary Methods, Tables and Figures Supplementary Table 1: Summary of whole genome sequencing results including performance metrics and time to reporting (N=62). Supplementary Table 2: Summary of GATA6 RNA in situ results and its correlation with RNA subtype and histologic grade. Supplementary Figure 1: WGS Performance Characteristics. Supplementary Figure 2: Both COMP-0037 and COMP-0057 had germline BRCA2 p.S1982fs mutations but only COMP-0037 had a second hit (somatic LOH of wild type allele) and showed hallmarks of double strand break repair deficiency. Supplementary Figure 3: BRCA2 mutation status of COMP-0057. Supplementary Figure 4: Subtypes of advanced PDAC by Moffitt tumour classification Supplementary Figure 5: Correlation between Moffitt tumor RNA subtypes and GATA6 gene expression. Supplementary Figure 6: Correlation between GATA6 expression measured by RNASeq and RNA in situ hybridization. Supplementary Figure 7: Differentially expressed pathways between Moffitt's basal like and classical RNA subtypes Supplementary Figure 8: CDK4 amplification identified in COMP-0008 (A) and CDK6 amplification identified in COMP-0010 (B) validated by fluorescence in-situ hybridization.

Published
2023

43. Supplementary Figure 6 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 6 shows the tumour ploidy analysis of xenografts evaluated in the preclinical trial that were not whole genome sequenced

Published
2023

44. Supplementary Figure 2 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 2 shows the results of a pilot monotherapy trial to evaluate regimen-related toxicity

Published
2023

45. Supplementary Table 3 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Table 3 shows the establishment of primary cell cultures from HRD PDAC xenografts

Published
2023

46. Data from Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics

Author

David F. Schaeffer, Daniel J. Renouf, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Steven Gallinger, Jennifer J. Knox, Rachel Goodwin, Patricia A. Tang, Oliver Bathe, Julie M. Wilson, Jonathan M. Loree, Faiyaz Notta, Andrew J. Mungall, Richard A. Moore, Grainne M. O'Kane, Hui-li Wong, Steve E. Kalloger, Erica S. Tsang, Robert E. Denroche, Gun Ho Jang, Laura M. Williamson, Veronika Csizmok, Michael K.C. Lee, Joanna M. Karasinska, and James T. Topham

Abstract

Purpose:RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice.Experimental Design:Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival.Results:Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001).Conclusions:Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.

Published
2023

47. Supplementary Table 1 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Table 1 shows the clinical characteristics of the patients from whom patient-derived xenografts were generated and evaluated in the preclinical trial

Published
2023

48. Data from A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer

Author

Steven Gallinger, George Zogopoulos, Yifan Wang, Ashton Connor, Jennifer J. Knox, Julie M. Wilson, Grainne M. O'Kane, Susan J. Done, Pamela S. Ohashi, Faiyaz Notta, Tracy L. McGaha, Rama Khokha, Peter Bronsert, Foram Vyas, Dianne Chadwick, Sheng-Ben Liang, Sharon Dhaliwal, Niandong Li, Jing Xu, John M.S. Bartlett, Angela De Luca, Ilinca M. Lungu, Robert E. Denroche, Amy Zhang, Sandra E. Fischer, Mehdi Masoomian, Aaditeya Jhaveri, Prashant P. Bavi, Gun-Ho Jang, Barbara Grünwald, and Joan M. Romero

Abstract

Purpose:The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.Experimental Design:Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.Results:Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this “4-chemokine signature” positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell–inflamed phenotype across primary PDAC and PDAC liver metastases.Conclusions:A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

Published
2023

49. Supplementary Data from Altered Gene Expression along the Glycolysis–Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer

Author

David F. Schaeffer, Daniel J. Renouf, Steven J.M. Jones, Marco A. Marra, Janessa Laskin, Steven Gallinger, Jennifer J. Knox, Faiyaz Notta, Andrew Metcalfe, Cassia Warren, Malcolm J. Moore, Andrew J. Mungall, Richard A. Moore, Grainne M. O'Kane, Michael K.C. Lee, Hui-Li Wong, Laura M. Williamson, Luka Culibrk, Robert E. Denroche, Gun Ho Jang, Steve E. Kalloger, James T. Topham, and Joanna M. Karasinska

Abstract

Supplemental Figures and Tables

Published
2023

50. Supplementary Figure 8 from A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Author

George Zogopoulos, Steven Gallinger, Jennifer J. Knox, Sandra E. Fischer, Grainne M. O'Kane, Talia Golan, William D. Foulkes, Paz Polak, Celia M.T. Greenwood, James Biagi, David Valenti, Louis-Martin Boucher, Tatiana Cabrera, Nathaniel Bouganim, Jamil Asselah, Yasser Riazalhosseini, Zu-Hua Gao, Julie M. Wilson, John M.S. Bartlett, Ilinca M. Lungu, Mehdi Masoomian, Simeng Bu, Chani Stossel, Spring Holter, Ayelet Borgida, Robert C. Grant, Maria Raitses-Gurevich, Jean Monlong, Celine Domecq, Adeline Cuggia, Amy Zhang, Gun Ho Jang, Robert E. Denroche, Alain Pacis, Jin Yong Patrick Park, and Yifan Wang

Abstract

Supplementary Figure 8 shows the principal component analysis followed by k-means clustering to group xenografts based on their sensitivity to cisplatin, talazoparib and cisplatin-talazoparib

Published
2023

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