bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–03–31
seven papers selected by
Sergio Marchini, Humanitas Research
  1. Targeted and shallow whole genome sequencing identifies therapeutic opportunities in p53abn endometrial cancers.
  2. Embracing cancer complexity: Hallmarks of systemic disease.
  3. Novel Molecular Targets in Endometrial Cancer: Mechanisms and Perspectives for Therapy.
  4. Navigating the landscapes of spatial transcriptomics: How computational methods guide the way.
  5. How BRCA and homologous recombination deficiency change therapeutic strategies in ovarian cancer: a review of literature.
  6. Global epidemiology of epithelial ovarian cancer.
  7. Investigating the Spatial Distribution of Proliferating Cells in Primary Ovarian Cancers.
  1. Clin Cancer Res. 2024 Mar 27.
    Targeted and shallow whole genome sequencing identifies therapeutic opportunities in p53abn endometrial cancers.
    Amy Jamieson, Juliana Sobral de Barros, Dawn R Cochrane, J Maxwell Douglas, Sameer Shankar, Branden J Lynch, Samuel Leung, Spencer Martin, Janine Senz, Amy Lum, Yvette Drew, C Blake Gilks, David G Huntsman, Jessica N McAlpine.
       PURPOSE: Shallow whole genome sequencing (sWGS) can detect copy number (CN) aberrations. In high-grade serous ovarian (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers (ECs) to identify additional prognostic stratification and therapeutic opportunities.
    EXPERIMENTAL DESIGN: sWGS and targeted panel sequencing was performed on formalin-fixed paraffin-embedded p53abn ECs. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed.
    RESULTS: In 187 p53abn ECs, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. 22% potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with a high ploidy state, and CCNE1, ERBB2 and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. 28% of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. 34% of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on immunohistochemistry, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations.
    CONCLUSIONS: sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3689
  2. Cell. 2024 Mar 28. pii: S0092-8674(24)00175-2. [Epub ahead of print]187(7): 1589-1616
    Embracing cancer complexity: Hallmarks of systemic disease.
    Charles Swanton, Elsa Bernard, Chris Abbosh, Fabrice André, Johan Auwerx, Allan Balmain, Dafna Bar-Sagi, René Bernards, Susan Bullman, James DeGregori, Catherine Elliott, Ayelet Erez, Gerard Evan, Mark A Febbraio, Andrés Hidalgo, Mariam Jamal-Hanjani, Johanna A Joyce, Matthew Kaiser, Katja Lamia, Jason W Locasale, Sherene Loi, Ilaria Malanchi, Miriam Merad, Kathryn Musgrave, Ketan J Patel, Sergio Quezada, Jennifer A Wargo, Ashani Weeraratna, Eileen White, Frank Winkler, John N Wood, Karen H Vousden, Douglas Hanahan.
      The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.
    DOI:  https://doi.org/10.1016/j.cell.2024.02.009
  3. Biologics. 2024 ;18 79-93
    Novel Molecular Targets in Endometrial Cancer: Mechanisms and Perspectives for Therapy.
    Pamela Soberanis Pina, Stephanie Lheureux.
      Endometrial cancer (EC) has a high epidemiological impact with incidence and mortality rising worldwide. In recent years, the integration of the pathologic and molecular classification has provided relevant information to understand the heterogeneity in the biology of EC, which led to the evolution in the management of patients. Currently, therapeutic breakthroughs have been made in advanced EC to improve oncologic outcomes, with efforts to include patient reported outcomes. Precision and personalized medicine are under way in EC exploring different combination approaches to target cross-talk pathways, cancer cell microenvironment, and metabolic vulnerabilities and improve drug delivery. Yet, collaborative efforts are needed to face the challenges in practice by refining patient selection, ideal biomarker identification, and de-escalation of therapies according to emerging molecular and genomic features of EC.
    Keywords:  endometrial cancer; molecular targets; precision medicine; targeted therapy
    DOI:  https://doi.org/10.2147/BTT.S369783
  4. Wiley Interdiscip Rev RNA. 2024 Mar-Apr;15(2):15(2): e1839
    Navigating the landscapes of spatial transcriptomics: How computational methods guide the way.
    Runze Li, Xu Chen, Xuerui Yang.
      Spatially resolved transcriptomics has been dramatically transforming biological and medical research in various fields. It enables transcriptome profiling at single-cell, multi-cellular, or sub-cellular resolution, while retaining the information of geometric localizations of cells in complex tissues. The coupling of cell spatial information and its molecular characteristics generates a novel multi-modal high-throughput data source, which poses new challenges for the development of analytical methods for data-mining. Spatial transcriptomic data are often highly complex, noisy, and biased, presenting a series of difficulties, many unresolved, for data analysis and generation of biological insights. In addition, to keep pace with the ever-evolving spatial transcriptomic experimental technologies, the existing analytical theories and tools need to be updated and reformed accordingly. In this review, we provide an overview and discussion of the current computational approaches for mining of spatial transcriptomics data. Future directions and perspectives of methodology design are proposed to stimulate further discussions and advances in new analytical models and algorithms. This article is categorized under: RNA Methods > RNA Analyses in Cells RNA Evolution and Genomics > Computational Analyses of RNA RNA Export and Localization > RNA Localization.
    Keywords:  artificial intelligence; bioinformatics; data mining; machine learning; spatial transcriptomics
    DOI:  https://doi.org/10.1002/wrna.1839
  5. Front Oncol. 2024 ;14 1335196
    How BRCA and homologous recombination deficiency change therapeutic strategies in ovarian cancer: a review of literature.
    Martina Arcieri, Veronica Tius, Claudia Andreetta, Stefano Restaino, Anna Biasioli, Elena Poletto, Giuseppe Damante, Alfredo Ercoli, Lorenza Driul, Anna Fagotti, Domenica Lorusso, Giovanni Scambia, Giuseppe Vizzielli.
      About 50% of High Grade Serous Ovarian Cancer exhibit a high degree of genomic instability due to mutation of genes involved in Homologous Recombination (HRD) and such defect accounts for synthetic lethality mechanism of PARP inhibitors (PARP-i). Several clinical trials have shown how BRCA and HRD mutational status profoundly affect first line chemotherapy as well as response to maintenance therapy with PARP-i, hence Progression Free Survival and Overall Survival. Consequently, there is urgent need for the development of increasingly reliable HRD tests, overcoming present limitations, as they play a key role in the diagnostic and therapeutic process as well as have a prognostic and predictive value. In this review we offer an overview of the state of the art regarding the actual knowledge about BRCA and HRD mutational status, the rationale of PARPi use and HRD testing (current and in development assays) and their implications in clinical practice and in the treatment decision process, in order to optimize and choose the best tailored therapy in patients with ovarian cancer.
    Keywords:  BRCA protein; BRCAness; HRD testing; PARP inhibitors; homologous recombination deficiency; ovarian cancer; overall survival
    DOI:  https://doi.org/10.3389/fonc.2024.1335196
  6. Nat Rev Clin Oncol. 2024 Mar 28.
    Global epidemiology of epithelial ovarian cancer.
    Penelope M Webb, Susan J Jordan.
      Globally, ovarian cancer is the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020. Until the early 2000s, age-standardized incidence was highest in northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of eastern Europe and Asia. Ovarian cancer is a very heterogeneous disease and, even among the most common type, namely epithelial ovarian cancer, five major clinically and genetically distinct histotypes exist. Most high-grade serous ovarian carcinomas are now recognized to originate in the fimbrial ends of the fallopian tube. This knowledge has led to more cancers being coded as fallopian tube in origin, which probably explains some of the apparent declines in ovarian cancer incidence, particularly in high-income countries; however, it also suggests that opportunistic salpingectomy offers an important opportunity for prevention. The five histotypes share several reproductive and hormonal risk factors, although differences also exist. In this Review, we summarize the epidemiology of this complex disease, comparing the different histotypes, and consider the potential for prevention. We also discuss how changes in the prevalence of risk and protective factors might have contributed to the observed changes in incidence and what this might mean for incidence in the future.
    DOI:  https://doi.org/10.1038/s41571-024-00881-3
  7. Discov Med. 2024 Mar;36(182): 632-645
    Investigating the Spatial Distribution of Proliferating Cells in Primary Ovarian Cancers.
    Mohamed A A A Hegazi, Fabio Pasqualini, Gianluigi Taverna, Robert S Bresalier, Maurizio Chiriva-Internati, Fabio Grizzi.
       BACKGROUND: Ovarian cancer (OC) accounts for about 4% of female cancers globally. While Ki67-immunopositive (Ki67+) cell density is commonly used to assess proliferation in OC, the two-dimensional (2D) distribution pattern of these cells is poorly understood. This study explores the 2D distribution pattern of Ki67+ cells in primary OC tissues and models the proliferation process to improve our understanding of this hallmark of cancer.
    METHODS: A total of 100 tissue cores, included in a tissue microarray (TMA) representing 5 clear cell carcinomas, 62 serous carcinomas, 10 mucinous adenocarcinomas, 3 endometrioid adenocarcinomas, 10 lymph node metastases from OC, and 10 samples of adjacent normal ovary tissue, were stained using a standardized immunohistochemical protocol. The computer-aided image analysis system assessed the 2D distribution pattern of Ki67+ proliferating cells, providing the cell number and density, patterns of randomness, and cell-to-cell closeness. Three computer models were created to simulate behavior and responses, aiming to gain insights into the variations in the proliferation process.
    RESULTS: Significant differences in Ki67+ cell density were found between low- and high-grade serous carcinoma/mucinous adenocarcinomas (p = 0.003 and p = 0.01, respectively). The Nearest Neighbor Index of Ki67+ cells differed significantly between high-grade serous carcinomas and endometrioid adenocarcinomas (p = 0.01), indicating distinct 2D Ki67+ distribution patterns. Proxemics analysis revealed significant differences in Ki67+ cell-to-cell closeness between low- and high-grade serous carcinomas (p = 0.002). Computer models showed varied effects on the overall organization of Ki67+ cells and the ability to preserve the original 2D distribution pattern when altering the location and/or density of Ki67+ cells.
    CONCLUSIONS: Cell proliferation is a hallmark of OCs. This study provides new evidence that investigating the Ki67+ cell density and 2D distribution pattern can assist in understanding the proliferation status of OCs. Moreover, our computer models suggest that changes in Ki67+ cell density and their location are critical for maintaining the 2D distribution pattern.
    Keywords:  Ki67; distribution pattern; ovarian cancer; proliferation; spatial analysis; topography
    DOI:  https://doi.org/10.24976/Discov.Med.202436182.60
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