ORCID Profile
0000-0003-1223-0121
Current Organisations
Peter MacCallum Cancer Centre
,
University of Melbourne
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Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2023
DOI: 10.1158/1055-9965.EPI-22-0941
Abstract: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 P = 0.015 N = 325 published set HR, 2.87 95% CI, 2.17–3.81 P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599 HR, 2.22 95% CI, 1.66–2.95 P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis. Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2022
DOI: 10.1200/JCO.21.02108
Abstract: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66% 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494843
Abstract: Supplementary Table 6: Multivariate Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S42003-019-0741-7
Abstract: Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1 , but not MALAT1 . Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494849
Abstract: Supplementary Table 4: Multivariate Modeling of Methylation Signature Among Studies with Multiple Datatypes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494849.V1
Abstract: Supplementary Table 4: Multivariate Modeling of Methylation Signature Among Studies with Multiple Datatypes
Publisher: Springer Science and Business Media LLC
Date: 10-05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1078-0432.CCR-18-3691
Abstract: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival (N = 5) or had a very short time to progression (N = 5). The majority of mixed OCCC (N = 6, 85.7%) and a small proportion of pure OCCC (N = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS (P = 0.0194 and 0.0395, respectively). Mutations in ARID1A, PIK3CA, PPP2R1A, and TP53 were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome.
Publisher: American Association for Cancer Research (AACR)
Date: 20-06-2023
DOI: 10.1158/1078-0432.CCR-22-3815
Abstract: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P & 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 P & 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494861.V1
Abstract: Supplementary Table 1: Characteristics of Study Participants with High Grade Serous Tubo-Ovarian Carcinoma by Contributing Study
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/1078-0432.C.6740546
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden ( i POLE /i mut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival i P /i 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the i no specific molecular profile /i (NSMP) subtype, where immune infiltrates lacking B cells (TIL sub B minus /sub ) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 i P /i 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22545056
Abstract: Supplementary Data from The Tumor Microenvironment of Clear-Cell Ovarian Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494846
Abstract: Supplementary Table 5: Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data, excluding data from Previously Published Participants
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13983-9
Abstract: Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.
Publisher: Elsevier BV
Date: 03-2023
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
DOI: 10.1158/1557-3265.OVCA19-IA05
Abstract: A majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of approximately 40%, and less than 10% survive more than 10 years. Profound genomic instability, treatment with DNA-damaging drugs, and a large tumor burden promote the development of acquired resistance in a large proportion of patients, including multiple convergent resistant events within in iduals. Despite the propensity of HGSC to develop drug resistance, a small proportion of patients with advanced disease at diagnosis become long-term survivors. These exceptional patients include those who had suboptimal surgical clearance, and therefore were not cured surgically, and others who have had no evidence of disease recurrence following initial surgery and adjuvant chemotherapy. Our study, which is part of the international collaborative Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG), seeks to identify molecular, immunologic, and epidemiologic factors that influence long-term survival in HGSC. This presentation describes our genomic and immunologic analysis of exceptional survival of this deadly disease. Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline s les (median 39x coverage) of 55 long-term survivors. Primary tumor s les were also characterized by RNA sequencing, DNA methylation profiling, and immunohistochemistry. Thirty-eight (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemosensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls. Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related), and Signatures 5, 8, and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207 P = 0.001). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P & 0.001) compared to patients with RB1-positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P & 0.001). Multiplexed immunohistochemical analysis with immune cell panels demonstrated distinct associations with long-term survivors. This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations are associated with enhanced host immune responses and long-term survival. Citation Format: Dale Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje Wouters, Flurina Saner, Catherine Kennedy, Celeste Pearce, Malcolm Pike, Susan Ramus, Martin Kobel, Anna deFazio, Ellen Goode, Brad Nelson, David Bowtell. Molecular analysis of exceptional response in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research 2019 Sep 13-16, 2019 Atlanta, GA. Philadelphia (PA): AACR Clin Cancer Res 2020 (13_Suppl):Abstract nr IA05.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-019-1913-9
Abstract: A key mutational process in cancer is structural variation, in which rearrangements delete, lify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494846.V1
Abstract: Supplementary Table 5: Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data, excluding data from Previously Published Participants
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1538-7445.AM2018-LB-378
Abstract: Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of & % in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene lification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer. Citation Format: Isidro Cortés-Ciriano, June-Koo Lee, Ruibin Xi, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry Gordenin, Leszek J. Klimczak, Cheng-Zhong Zhang, David S. Pellman, Peter J. Park. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018 2018 Apr 14-18 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2018 (13 Suppl):Abstract nr LB-378.
Publisher: Wiley
Date: 21-10-2009
Abstract: Malignant tumours are often characterised by significant rearrangement of the genome. This may be visible in the form of a deranged karyotype with both loss and gain of DNA sequences extending from chromosomal regions to whole chromosomes. In several tumour types, however, gross genomic derangements are minimal, and tumour cells contain one or more additional (supernumerary) chromosomes that may be unrecognisable in terms of a single origin. In this review we term such chromosomes cancer-associated neochromosomes (CaNCs). In the absence of other identified genomic abnormalities, and because the CaNC is a common feature of the cancer type, it is hypothesised that the genetic alterations required for cell transformation are contained within its structure. In this review, we discuss the potential impact of modern genomic technologies on our understanding of the nature and causes of CaNC formation, which is central to several cancer types, exemplified here by well-differentiated liposarcoma.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2023
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494852.V1
Abstract: Supplementary Table 3: Differential Methylation Analysis for Mayo Training and Testing Sets for all QC-passed CpG loci from 450k
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494858.V1
Abstract: Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471188
Abstract: Supplementary Tables
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13825-8
Abstract: In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor s les and 88% and 83% respectively on independent primary and metastatic s les, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494876
Abstract: Supplementary Figure 1: Methylation Signature Approximation
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.YGYNO.2022.10.022
Abstract: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494870
Abstract: Supplementary Figure 3: Immune Analysis
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471185
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494873
Abstract: Supplementary Figure 2: No Association between Methylation Signature and Baseline Clinical Factors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471188.V1
Abstract: Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 08-2018
DOI: 10.1158/1557-3265.OVCA17-IA12
Abstract: High-grade serous ovarian cancer (HGSC) was one of the first cancer types subjected to comprehensive genomic analysis, and over the last 5-7 years gene expression and DNA sequence data have been generated from hundreds of s les. A large majority of this data has been obtained from surgical s les collected following primary debulking surgery or following a few cycles of neoadjuvant chemotherapy. By contrast, comparatively little data exist from patients who have been extensively treated with chemotherapy or newer targeted agents, such as antiangiogenics or PARP inhibitors (PARPi). Of particular interest are s les collected from patients whose cancer was initially responsive to treatment but has become resistant to therapy (acquired resistance) at the time of collection. The presentation will describe data obtained from whole-genome (N=73 s les, 36 patients) and targeted (N=65 s les, 48 patients) sequence analysis of recurrent or end-stage HGSC s les, focusing in particular on two mechanisms of acquired resistance–fusions involving the ABCB1 gene and reversion of germline BRCA1/2 mutations. ABCB1 encodes the multidrug resistance transporter MDR1, also known as P-glycoprotein. Data will be presented on the frequency and mechanisms of ABCB1 deregulation in recurrent HGSC, and approaches to clinical intervention in fusion-positive patients. Reversions in BRCA1/2 appear to render tumors that were defective in homologous recombination (HR) repair, HR proficient and therefore may have important implications for likely treatment response. The presentation will also discuss approaches to evaluating reversion status in patients with mutation in BRCA1/2. Citation Format: Elizabeth L. Christie, Jessica Beach, Dariush Etemadmoghadam, Dale Garsed, Ann-Marie Patch, Sian Fereday, Swetansu Pattnaik, Australian Ovarian Cancer Study, Samuel Brady, Andrea Bild, David D.L. Bowtell. Acquired chemotherapy resistance in high-grade serous ovarian cancer patients. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment Oct 1-4, 2017 Pittsburgh, PA. Philadelphia (PA): AACR Clin Cancer Res 2018 (15_Suppl):Abstract nr IA12.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13929-1
Abstract: The discovery of driver mutations is one of the key motivations for cancer genome sequencing. Here , as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across multiple tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2583 cancer genomes from the PCAWG project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Working Group, DriverPower has the highest F1 score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1038/S41588-022-01230-9
Abstract: Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor s les, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1538-7445.AM2019-2722
Abstract: Purpose: The majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of ~30%. However, a subset of patients have an extraordinary response to treatment and ~15% survive more than ten years (long-term survivors). The Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG) aims to uncover factors that influence long-term survival of HGSC patients. Here, we investigated the genomic and immunologic determinants of exceptional survival of this deadly disease. Experimental Design: Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline s les (median 39x coverage) of 55 long-term survivors. Primary tumor s les were also characterised by RNA sequencing, DNA methylation profiling and immunohistochemistry. Results: A total 38 (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemo-sensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression-free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls (316 unselected HGSC patients in The Cancer Genome Atlas). Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related) and Signatures 5, 8 and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207 P = 0.001). Staining of adjacent tumor tissue revealed that RB1 loss was associated with increased numbers of PD-1+ tumor-infiltrating lymphocytes (P = 0.015) and MHC class I on tumor cells (P = 0.002). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P & 0.001) compared to patients with RB1 positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P & 0.001). Conclusions: This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations might be associated with enhanced host immune responses and long-term survival. Citation Format: Dale W. Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje C. Wouters, Flurina Saner, Jessica A. Beach, Katy Milne, Catherine J. Kennedy, Joy Hendley, Nadia Traficante, Celeste L. Pearce, Malcolm C. Pike, Multidisciplinary Ovarian Cancer Outcomes Group, Susan J. Ramus, Martin Köbel, Brad H. Nelson, Ellen L. Goode, Anna deFazio, David D. Bowtell. The genomic landscape of high-grade serous ovarian cancer in long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2019 (13 Suppl):Abstract nr 2722.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-019-1907-7
Abstract: Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of s les. A nearly fourfold ersification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S41467-020-17359-2
Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179
Abstract: Supplementary methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494876.V1
Abstract: Supplementary Figure 1: Methylation Signature Approximation
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14351-8
Abstract: We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real s les, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494864
Abstract: Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature
Publisher: American Association for Cancer Research (AACR)
Date: 12-09-2022
DOI: 10.1158/2326-6066.CIR-22-0407
Abstract: Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating “TGFβ remodeling of the extracellular matrix” as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.CCELL.2014.09.010
Abstract: We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is lified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, lified oncogenes are overexpressed, while co lified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, lification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2018
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41588-019-0562-0
Abstract: About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of s les and spanned a range of event types. Long interspersed nuclear element (LINE-1 L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level lification of oncogenes. These observations illuminate a relevant role of 22 L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494861
Abstract: Supplementary Table 1: Characteristics of Study Participants with High Grade Serous Tubo-Ovarian Carcinoma by Contributing Study
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676032
Abstract: Supplementary Tables S1-S5
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676035.V1
Abstract: Supplementary Figures S1-S4
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676035
Abstract: Supplementary Figures S1-S4
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471185.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494867
Abstract: Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41467-020-18151-Y
Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA s les, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological ergences between two reproducible somatic variant detection efforts.
Publisher: SAGE Publications
Date: 2018
Abstract: High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients. Penalized regression models of germline variation, with or without methylation, did not reveal a role in HGSOC gene expression. However, we observed significant association between regional methylation and expression of 5 genes ( WDPCP, KRT6C, BRCA2, EFCAB13, and ZNF283). CpGs retained in ENET model for BRCA2 and ZNF283 appeared enriched in several regulatory elements, suggesting that regularized regression may provide a novel utility for integrative genomic analysis.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2017
DOI: 10.1158/1538-7445.AM2017-3368
Abstract: High grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with gene mutation, DNA methylation changes, genetic variation, and epigenetic processes. Variation in several susceptibility regions and cancer-typical global methylation patterns have been observed in HGSOC however, this knowledge has not been compelling in understanding HGSOC intiation or progression. As ingetration of genomic, epigenomic, and transcriptomic data has increased mechanistic understanding in other cancers, we hypothesized that tumor methylation alone or in combination with germline genetic variation influences tumor gene expression in HGSOC. We examined three nested models using an Elastnic Net (ENET) penalized regression method while adjusting for somatic copy number (CNV): a) germline genotype and tumor DNA methylation (full model), b) genotype only, and c) DNA methylation only. We included 339 cases from The Cancer Genome Atlas (TCGA), 54 cases from Mayo Clinic, and 78 cases from the Australian Ovarian Cancer Study (AOCS). Genotyping and copy number calls on germline DNA, expression, methylation and copy number on somatic s les were collected and analyzed on different platforms separately at each study site. We excluded genes with low overall expression and thus analyzed a total of 11,922 genes available in three datasets ( Ensembl IDs, 500kb window up- and downstream). In general, combining genomic data in HGSOC did not reveal a role for germline genetic variation in altering gene expression. However, in methylation only models 79 genes were associated with differential expression in the TCGA cases (permutation multiple testing adjusted p-val & .05), in the Mayo cases (unadjusted p-val & .05) and AOCS cases (unadjusted p-val & .05). A known tummor suppressor (FBXW7) was associated with differential expression in the three datasets at p-val & .01. This work demonstrates the feasibility, utility, and statistical power of ENET gene-level analyses incoporating maximal genomic information. Citation Format: Yanina Natanzon, Madalene Earp, Julie M. Cunningham, Kimberly R. Kalli, Stacey J. Winham, Sebastian M. Armasu, Melissa C. Larson, Chen Wang, David D. Bowtell, Dale W. Garsed, Ellen Goode. Omics data integration analysis in high grade serous ovarian cancer: results from three studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2017-3368
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494867.V1
Abstract: Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.C.6740546.V1
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden ( i POLE /i mut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival i P /i 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the i no specific molecular profile /i (NSMP) subtype, where immune infiltrates lacking B cells (TIL sub B minus /sub ) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 i P /i 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study. /
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1965-X
Abstract: The discovery of drivers of cancer has traditionally focused on protein-coding genes 1–4 . Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of in idual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers 6,7 , raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53 , in the 3′ untranslated regions of NFKBIZ and TOB1 , focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional ex les of these drivers will be found as more cancer genomes become available.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550844.V1
Abstract: Abstract Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of i ARID1A /i -wildtype (ARID1A sup wt /sup ) versus i ARID1A /i -mutant (ARID1A sup mut /sup ) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138 sup + /sup plasma cells, the LE had more CD20 sup + /sup B cells and T cells, whereas the stroma had more mast cells and αSMA sup + /sup fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating “TGFβ remodeling of the extracellular matrix” as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1A sup wt /sup and ARID1A sup mut /sup CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8 sup + /sup T cells within the MCA and CD4 sup + /sup T cells at the LE and stroma significantly associated with decreased overall survival. /
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802.V1
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14367-0
Abstract: The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53 , TLE4 , and TCF4 . We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and s les containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as s les with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494873.V1
Abstract: Supplementary Figure 2: No Association between Methylation Signature and Baseline Clinical Factors
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2224
Abstract: Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first ex le of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res 77(16) 4268–78. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494852
Abstract: Supplementary Table 3: Differential Methylation Analysis for Mayo Training and Testing Sets for all QC-passed CpG loci from 450k
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13824-9
Abstract: Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , we dissect whole-genome sequencing data of over 2500 matched tumor-control s les from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX trunc ) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor s les contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX trunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.
Publisher: BMJ Publishing Group Ltd
Date: 11-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22545056.V1
Abstract: Supplementary Data from The Tumor Microenvironment of Clear-Cell Ovarian Cancer
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Society for Clinical Investigation
Date: 15-11-2013
DOI: 10.1172/JCI70559
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676032.V1
Abstract: Supplementary Tables S1-S5
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494864.V1
Abstract: Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.C.6534651.V1
Abstract: AbstractBackground: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8 sup + /sup tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors ( i N /i = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 i P /i = 0.015 i N /i = 325 published set HR, 2.87 95% CI, 2.17–3.81 i P /i = 2.2 × 10 sup −13 /sup ) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression ( i N /i = 599 HR, 2.22 95% CI, 1.66–2.95 i P /i = 4.1 × 10 sup −8 /sup ). Methylation signature was inversely related to CD8 sup + /sup TIL levels ( i P /i = 2.4 × 10 sup −7 /sup ) and TAP1 expression ( i P /i = 0.0011) and was associated with gene expression molecular subtype ( i P /i = 5.9 × 10 sup −4 /sup ) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. /
Publisher: Elsevier BV
Date: 12-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494858
Abstract: Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach
Publisher: Springer Science and Business Media LLC
Date: 08-06-2012
DOI: 10.1007/S00428-012-1256-5
Abstract: While surgery is the usual treatment for localized well-differentiated and dedifferentiated liposarcomas (WDLPS/DDLPS), the therapeutic options for patients with advanced disease are limited. The classical antimitotic treatments are most often inefficient. The establishment of genetically characterized cell lines is therefore crucial for providing in vitro models for novel targeted therapies. We have used spectral karyotyping, fluorescence in situ hybridization with whole chromosome painting and locus-specific probes, and array-comparative genomic hybridization to identify the chromosomal and molecular alterations of a novel cell line established from a recurring sclerosing WDLPS. The karyotype was hypertriploid and showed multiple structural anomalies. All cells retained the presence of a giant marker chromosome that had been previously identified in the primary cell cultures. This giant chromosome contained high-level lification of chromosomal regions 12q13-21 and lacked the alpha-satellite centromeric sequences associated with WDLPS/DDLPS. The 12q licon was large, containing 370 lified genes. The DNA copy number ranged from 3 to 57. The highest levels of lification were observed at 12q14.3 for GNS, WIF1, and HMGA2. We analyzed the mRNA expression status by real-time reverse transcription polymerase chain reaction for six genes from this licon: MDM2, HMGA2, CDK4, TSPAN31, WIF1, and YEATS4. mRNA overexpression was correlated with genomic lification. A second licon originating from 10p11-14 was also present in the giant marker chromosome. The 10p licon contained 62 genes, including oncogenes such as MLLT10, previously described in chimeric fusion with MLL in leukemias, NEBL, and BMI1.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.C.6534651
Abstract: AbstractBackground: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8 sup + /sup tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors ( i N /i = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 i P /i = 0.015 i N /i = 325 published set HR, 2.87 95% CI, 2.17–3.81 i P /i = 2.2 × 10 sup −13 /sup ) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression ( i N /i = 599 HR, 2.22 95% CI, 1.66–2.95 i P /i = 4.1 × 10 sup −8 /sup ). Methylation signature was inversely related to CD8 sup + /sup TIL levels ( i P /i = 2.4 × 10 sup −7 /sup ) and TAP1 expression ( i P /i = 0.0011) and was associated with gene expression molecular subtype ( i P /i = 5.9 × 10 sup −4 /sup ) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494843.V1
Abstract: Supplementary Table 6: Multivariate Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-14052-X
Abstract: Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53 , MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41588-019-0564-Y
Abstract: Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494870.V1
Abstract: Supplementary Figure 3: Immune Analysis
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-019-13885-W
Abstract: The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT , MDM2 , CDK4 , ERBB2 , CD274 , PDCD1LG2 , and IGF2 . TERT -associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non- lified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2015
DOI: 10.1038/NATURE14410
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA s les from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 lification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in in idual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179.V1
Abstract: Supplementary methods
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550844
Abstract: Abstract Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of i ARID1A /i -wildtype (ARID1A sup wt /sup ) versus i ARID1A /i -mutant (ARID1A sup mut /sup ) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138 sup + /sup plasma cells, the LE had more CD20 sup + /sup B cells and T cells, whereas the stroma had more mast cells and αSMA sup + /sup fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating “TGFβ remodeling of the extracellular matrix” as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1A sup wt /sup and ARID1A sup mut /sup CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8 sup + /sup T cells within the MCA and CD4 sup + /sup T cells at the LE and stroma significantly associated with decreased overall survival. /
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14352-7
Abstract: The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour s le. In simulations, we find TrackSig has a 3–5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.
No related grants have been discovered for Dale Garsed.