bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022–04–03
fourteen papers selected by
Sergio Marchini, Humanitas Research
  1. Bevacizumab versus PARP-inhibitors in women with newly diagnosed ovarian cancer: a network meta-analysis.
  2. Mutant p53: it's not all one and the same.
  3. Integrating circulating-free DNA (cfDNA) analysis into clinical practice: opportunities and challenges.
  4. Genomic landscape of endometrial carcinomas of no specific molecular profile.
  5. Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates.
  6. PARPs: All for One and One for All? Enhancing Diversity in Clinical Trials.
  7. classifieR a flexible interactive cloud-application for functional annotation of cancer transcriptomes.
  8. Inferring gene expression from cell-free DNA fragmentation profiles.
  9. Clinical relevance of tumour-associated macrophages.
  10. Quantitative PCR based method to assess cfDNA quality, adjust input mass, and improve next-generation sequencing assay performance.
  11. Tumor microenvironment manipulates chemoresistance in ovarian cancer (Review).
  12. Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder.
  13. Methylation and copy number profiling: emerging tools to differentiate osteoblastoma from malignant mimics?
  14. Unravelling the tumour genome: the evolutionary and clinical impacts of structural variants in tumourigenesis.
  1. BMC Cancer. 2022 Mar 30. 22(1): 346
    Bevacizumab versus PARP-inhibitors in women with newly diagnosed ovarian cancer: a network meta-analysis.
    Young Ju Suh, Banghyun Lee, Kidong Kim, Yujin Jeong, Hwa Yeon Choi, Sung Ook Hwang, Yong Beom Kim.
       BACKGROUND: In women with newly diagnosed ovarian cancer, bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) exhibit improved progression-free survival (PFS) when administered concurrent with chemotherapy and/or maintenance therapy, but no study has directly compared their effects. Therefore, this study aimed to compare the efficacy and safety of bevacizumab and PARPi in women with newly diagnosed ovarian cancer using a network meta-analysis.
    METHODS: PubMed, Medline, and Embase databases were searched, and five randomized trials assessing PFS in women with newly diagnosed ovarian cancer treated with either bevacizumab, PARPi, or placebo or no additional agent (controls) were identified. PFS was compared in the overall population with ovarian cancer, women with a BRCA1/2 mutation (BRCAm) and women with homologous-recombination deficiency (HRD). Adverse events (grade ≥ 3) were compared in all populations of the included studies.
    RESULTS: PARPi improved PFS significantly more than bevacizumab in women with a BRCAm (HR 0.47; 95% CI 0.36-0.60) and with HRD (HR 0.66; 95% CI 0.50-0.87). However, in the overall population with ovarian cancer, no significant difference in PFS was observed between women treated with PARPi and those treated with bevacizumab. PARPi exhibited the highest surface under the cumulative ranking probabilities value as the most effective treatment for PFS (PARPi vs. bevacizumab: 98% vs. 52% in the overall population with ovarian cancer; 100% vs. 50% in women with BRCAm; 100% vs. 50% in women with HRD). For adverse events, the risk of all treatments was similar. However, PARPi had a higher adverse risk than the control group (relative risk 2.14; 95% CI 1.40-3.26).
    CONCLUSIONS: In women with newly diagnosed ovarian cancer, PARPi might be more effective in terms of PFS compared to bevacizumab. The risk of serious adverse events was similar for PARPi and bevacizumab.
    Keywords:  Adverse events; BRCA mutation; Bevacizumab; Homologous recombination deficiency; Ovarian cancer; Poly(ADP-ribose) polymerase inhibitors; Progression-free survival
    DOI:  https://doi.org/10.1186/s12885-022-09455-x
  2. Cell Death Differ. 2022 Mar 31.
    Mutant p53: it's not all one and the same.
    Margaret C Kennedy, Scott W Lowe.
      Mutation of the TP53 tumor suppressor gene is the most common genetic alteration in cancer, and almost 1000 alleles have been identified in human tumors. While virtually all TP53 mutations are thought to compromise wild type p53 activity, the prevalence and recurrence of missense TP53 alleles has motivated countless research studies aimed at understanding the function of the resulting mutant p53 protein. The data from these studies support three distinct, but perhaps not necessarily mutually exclusive, mechanisms for how different p53 mutants impact cancer: first, they lose the ability to execute wild type p53 functions to varying degrees; second, they act as a dominant negative (DN) inhibitor of wild type p53 tumor-suppressive programs; and third, they may gain oncogenic functions that go beyond mere p53 inactivation. Of these possibilities, the gain of function (GOF) hypothesis is the most controversial, in part due to the dizzying array of biological functions that have been attributed to different mutant p53 proteins. Herein we discuss the current state of understanding of TP53 allele variation in cancer and recent reports that both support and challenge the p53 GOF model. In these studies and others, researchers are turning to more systematic approaches to profile TP53 mutations, which may ultimately determine once and for all how different TP53 mutations act as cancer drivers and whether tumors harboring distinct mutations are phenotypically unique. From a clinical perspective, such information could lead to new therapeutic approaches targeting the effects of different TP53 alleles and/or better sub-stratification of patients harboring TP53 mutant cancers.
    DOI:  https://doi.org/10.1038/s41418-022-00989-y
  3. Br J Cancer. 2022 Mar 26.
    Integrating circulating-free DNA (cfDNA) analysis into clinical practice: opportunities and challenges.
    Miguel García-Pardo, Maisam Makarem, Janice J N Li, Deirdre Kelly, Natasha B Leighl.
      In the current era of precision medicine, the identification of genomic alterations has revolutionised the management of patients with solid tumours. Recent advances in the detection and characterisation of circulating tumour DNA (ctDNA) have enabled the integration of liquid biopsy into clinical practice for molecular profiling. ctDNA has also emerged as a promising biomarker for prognostication, monitoring disease response, detection of minimal residual disease and early diagnosis. In this Review, we discuss current and future clinical applications of ctDNA primarily in non-small cell lung cancer in addition to other solid tumours.
    DOI:  https://doi.org/10.1038/s41416-022-01776-9
  4. Mod Pathol. 2022 Apr 01.
    Genomic landscape of endometrial carcinomas of no specific molecular profile.
    Amir Momeni-Boroujeni, Bastien Nguyen, Chad M Vanderbilt, Marc Ladanyi, Nadeem R Abu-Rustum, Carol Aghajanian, Lora H Ellenson, Britta Weigelt, Robert A Soslow.
      Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) as copy number-low (also referred to as "no specific molecular profile" [NSMP]) have a prognosis intermediate between POLE-mutated and copy number-high ECs. NSMP-ECs are a heterogeneous group, however, comprising both relatively indolent and aggressive ECs. We identified a total of 472 NSMP-ECs among 1,239 ECs that underwent clinical sequencing of 410-468 cancer-related genes. Somatic mutation and copy number alteration data were subjected to unsupervised hierarchical clustering, which identified three genomic clusters. Random sampling with stratification was used to choose ~80 endometrioid ECs from each cluster, resulting in a study size of 240 endometrioid ECs as well as an additional 44 non-endometrioid NSMP-ECs. Cluster 1 (C1, n = 80) consisted primarily of NSMP-ECs with PTEN and PIK3R1 mutations, Cluster 2 (C2, n = 81) of tumors with PTEN and PIK3CA mutations and Cluster 3 (C3, n = 79) of NSMP-ECs with chromosome 1q high-level gain and lack of PTEN mutations. The majority (72.7%) of non-endometrioid NSMP-ECs mapped to C3. NSMP-ECs from C3 were more likely to be FIGO grade 3 (30%), estrogen receptor-negative/weak (54.5%) and FIGO stages III or IV. In multivariate analysis, molecular clusters were associated with worse overall survival outcomes with C3 tumors having the worst (hazard ratio: 4) and C1 tumors having the best outcome. In conclusion, NSMP-ECs are a heterogenous group of tumors and comprise both aggressive and clinically low-risk ECs that can be identified based on mutation and copy number data.
    DOI:  https://doi.org/10.1038/s41379-022-01066-y
  5. Mod Pathol. 2022 Mar 28.
    Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates.
    Josephine K Dermawan, Fabio Vanoli, Laurie Herviou, Yun-Shao Sung, Lei Zhang, Samuel Singer, William D Tap, Ryma Benayed, Tejus A Bale, Jamal K Benhamida, Brendan C Dickson, Cristina R Antonescu.
      To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS::CREB translocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1/FUS fusion partners-ATF1, CREB1, and CREM-and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERT promoter and CDKN2A mutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/B homozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF, CDH19, PARVB, and PFKP was found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4 and XAF1 were differentially upregulated and hypomethylated in AFH but not CCS. Unsupervised clustering of methylation profiles revealed that CREB family translocation-associated tumors form neighboring but tight, distinct clusters. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.
    DOI:  https://doi.org/10.1038/s41379-022-01023-9
  6. Clin Cancer Res. 2022 Mar 31. pii: clincanres.0442.2022. [Epub ahead of print]
    PARPs: All for One and One for All? Enhancing Diversity in Clinical Trials.
    Shibani Nicum, Sarah P Blagden.
      PARP inhibitors have revolutionized the management of ovarian cancer and are being licenced for other cancer indications. The clinical trials prompting licencing decisions in ovarian cancer were dominated by white participants or participant ethnicity was not documented. To compensate for this, replicative studies like L-MOCA can be run in specific ethnic groups. In future, strategies such as mandatory collection and publication of race and ethnicity data are essential alongside concerted efforts to widen the inclusivity of trial recruitment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0442
  7. BMC Bioinformatics. 2022 Mar 31. 23(1): 114
    classifieR a flexible interactive cloud-application for functional annotation of cancer transcriptomes.
    Gerard P Quinn, Tamas Sessler, Baharak Ahmaderaghi, Shauna Lambe, Harper VanSteenhouse, Mark Lawler, Mark Wappett, Bruce Seligmann, Daniel B Longley, Simon S McDade.
       BACKGROUND: Transcriptionally informed predictions are increasingly important for sub-typing cancer patients, understanding underlying biology and to inform novel treatment strategies. For instance, colorectal cancers (CRCs) can be classified into four CRC consensus molecular subgroups (CMS) or five intrinsic (CRIS) sub-types that have prognostic and predictive value. Breast cancer (BRCA) has five PAM50 molecular subgroups with similar value, and the OncotypeDX test provides transcriptomic based clinically actionable treatment-risk stratification. However, assigning samples to these subtypes and other transcriptionally inferred predictions is time consuming and requires significant bioinformatics experience. There is no "universal" method of using data from diverse assay/sequencing platforms to provide subgroup classification using the established classifier sets of genes (CMS, CRIS, PAM50, OncotypeDX), nor one which in provides additional useful functional annotations such as cellular composition, single-sample Gene Set Enrichment Analysis, or prediction of transcription factor activity.
    RESULTS: To address this bottleneck, we developed classifieR, an easy-to-use R-Shiny based web application that supports flexible rapid single sample annotation of transcriptional profiles derived from cancer patient samples form diverse platforms. We demonstrate the utility of the " classifieR" framework to applications focused on the analysis of transcriptional profiles from colorectal (classifieRc) and breast (classifieRb). Samples are annotated with disease relevant transcriptional subgroups (CMS/CRIS sub-types in classifieRc and PAM50/inferred OncotypeDX in classifieRb), estimation of cellular composition using MCP-counter and xCell, single-sample Gene Set Enrichment Analysis (ssGSEA) and transcription factor activity predictions with Discriminant Regulon Expression Analysis (DoRothEA).
    CONCLUSIONS: classifieR provides a framework which enables labs without access to a dedicated bioinformation can get information on the molecular makeup of their samples, providing an insight into patient prognosis, druggability and also as a tool for analysis and discovery. Applications are hosted online at https://generatr.qub.ac.uk/app/classifieRc and https://generatr.qub.ac.uk/app/classifieRb after signing up for an account on https://generatr.qub.ac.uk .
    Keywords:  Cancer Subtype; Colorectal Shiny CMS CRIS Immune; Functional Annotation; Gene expression; Shiny application
    DOI:  https://doi.org/10.1186/s12859-022-04641-x
  8. Nat Biotechnol. 2022 Mar 31.
    Inferring gene expression from cell-free DNA fragmentation profiles.
    Mohammad Shahrokh Esfahani, Emily G Hamilton, Mahya Mehrmohamadi, Barzin Y Nabet, Stefan K Alig, Daniel A King, Chloé B Steen, Charles W Macaulay, Andre Schultz, Monica C Nesselbush, Joanne Soo, Joseph G Schroers-Martin, Binbin Chen, Michael S Binkley, Henning Stehr, Jacob J Chabon, Brian J Sworder, Angela B-Y Hui, Matthew J Frank, Everett J Moding, Chih Long Liu, Aaron M Newman, James M Isbell, Charles M Rudin, Bob T Li, David M Kurtz, Maximilian Diehn, Ash A Alizadeh.
      Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.
    DOI:  https://doi.org/10.1038/s41587-022-01222-4
  9. Nat Rev Clin Oncol. 2022 Mar 30.
    Clinical relevance of tumour-associated macrophages.
    Mikael J Pittet, Olivier Michielin, Denis Migliorini.
      In the past decade, substantial advances have been made in understanding the biology of tumour-associated macrophages (TAMs), and their clinical relevance is emerging. A particular aspect that is becoming increasingly clear is that the interaction of TAMs with cancer cells and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. Therefore, manipulation of TAMs could enable improved disease control in a substantial fraction of patients across a large number of cancer types. In this Review, we examine the diversity of TAMs in various cancer indications and how this heterogeneity is being revisited with the advent of single-cell technologies, and then explore the current knowledge on the functional roles of different TAM states and the prognostic and predictive value of TAM-related signatures. We also review agents targeting TAMs that are currently being or will soon be tested in clinical trials, and how manipulations of TAMs can improve existing anticancer treatments. Finally, we discuss how TAM-targeting approaches could be further integrated into routine clinical practice, considering a precision oncology approach and viewing TAMs as a dynamic population that can evolve under treatment pressure.
    DOI:  https://doi.org/10.1038/s41571-022-00620-6
  10. J Mol Diagn. 2022 Mar 29. pii: S1525-1578(22)00074-5. [Epub ahead of print]
    Quantitative PCR based method to assess cfDNA quality, adjust input mass, and improve next-generation sequencing assay performance.
    Seng Lor Saelee, Alexander F Lovejoy, Bernd Hinzmann, Katrina Mayol, Samantha Huynh, Amy Harrell, Josh Lefkowitz, Niharika Deodhar, Gladys Garcia-Montoya, Stephanie J Yaung, Daniel M Klass.
      Cell-free DNA (cfDNA) based testing has undergone increasingly wide adoption, including assays for detection of circulating tumor DNA (ctDNA). Due to nucleosome protection, cfDNA has a distinctive fragment size of 160-180 base pairs (bp). However, cfDNA can be contaminated with high molecular weight (HMW) genomic DNA (gDNA) from blood cells released in plasma during sample collection. Such contamination can lead to decreased sensitivity or inconsistent results when cfDNA next generation sequencing (NGS) assays are performed. This technical advancement describes a quantitative PCR method for HMW contamination assessment and input mass adjustment, and demonstrates its use to improve consistency of performance in a ctDNA NGS workflow.
    Keywords:  NGS; cfDNA; liquid biopsy
    DOI:  https://doi.org/10.1016/j.jmoldx.2022.02.005
  11. Oncol Rep. 2022 May;pii: 102. [Epub ahead of print]47(5):
    Tumor microenvironment manipulates chemoresistance in ovarian cancer (Review).
    Qiaoling Zhang, Jiashan Ding, Yingmei Wang, Linsheng He, Fengxia Xue.
      Ovarian cancer (OC) is the leading cause of mortality among the various types of gynecological cancer, and >75% of the cases are diagnosed at a late stage. Although platinum‑based chemotherapy is able to help the majority of patients to achieve remission, the disease frequently recurs and acquires chemoresistance, resulting in high mortality rates. The complexity of OC therapy is not solely governed by the intrinsic characteristics of the OC cells (OCCs) themselves, but is also largely dependent on the dynamic communication between OCCs and various components of their surrounding microenvironment. The present review attempts to describe the mutual interplay between OCCs and their surrounding microenvironment. Tumor‑associated macrophages (TAMs) and cancer‑associated fibroblasts (CAFs) are the most abundant stromal cell types in OC. Soluble factors derived from CAFs steadily nourish both the OCCs and TAMs, facilitating their proliferation and immune evasion. ATP binding cassette transporters facilitate the extrusion of cytotoxic molecules, eventually promoting cell survival and multidrug resistance. Extracellular vesicles fulfill their role as genetic exchange vectors, transferring cargo from the donor cells to the recipient cells and propagating oncogenic signaling. A greater understanding of the vital roles of the tumor microenvironment will allow researchers to be open to the prospect of developing therapeutic approaches for combating OC chemoresistance.
    Keywords:  ABC; CAF; EV; OC; chemoresistance; immune cells; microenvironment
    DOI:  https://doi.org/10.3892/or.2022.8313
  12. Nat Commun. 2022 Apr 01. 13(1): 1739
    Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder.
    Kangning Dong, Shihua Zhang.
      Recent advances in spatially resolved transcriptomics have enabled comprehensive measurements of gene expression patterns while retaining the spatial context of the tissue microenvironment. Deciphering the spatial context of spots in a tissue needs to use their spatial information carefully. To this end, we develop a graph attention auto-encoder framework STAGATE to accurately identify spatial domains by learning low-dimensional latent embeddings via integrating spatial information and gene expression profiles. To better characterize the spatial similarity at the boundary of spatial domains, STAGATE adopts an attention mechanism to adaptively learn the similarity of neighboring spots, and an optional cell type-aware module through integrating the pre-clustering of gene expressions. We validate STAGATE on diverse spatial transcriptomics datasets generated by different platforms with different spatial resolutions. STAGATE could substantially improve the identification accuracy of spatial domains, and denoise the data while preserving spatial expression patterns. Importantly, STAGATE could be extended to multiple consecutive sections to reduce batch effects between sections and extracting three-dimensional (3D) expression domains from the reconstructed 3D tissue effectively.
    DOI:  https://doi.org/10.1038/s41467-022-29439-6
  13. Mod Pathol. 2022 Mar 28.
    Methylation and copy number profiling: emerging tools to differentiate osteoblastoma from malignant mimics?
    Baptiste Ameline, Michaela Nathrath, Karolin H Nord, Felix Haglund de Flon, Judith V M G Bovée, Andreas H Krieg, Sylvia Höller, Jürgen Hench, Daniel Baumhoer.
      Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.
    DOI:  https://doi.org/10.1038/s41379-022-01071-1
  14. J Pathol. 2022 Mar 31.
    Unravelling the tumour genome: the evolutionary and clinical impacts of structural variants in tumourigenesis.
    Alhafidz Hamdan, Ailith Ewing.
      Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intra-tumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients. This article is protected by copyright. All rights reserved.
    Keywords:  chromothripsis; extra-chromosomal DNA; patient stratification; structural variants; tumour evolution; whole genome sequencing
    DOI:  https://doi.org/10.1002/path.5901
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