bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–07–28
twelve papers selected by
Sergio Marchini, Humanitas Research
  1. Spatial landscapes of cancers: insights and opportunities.
  2. Estimating sojourn time and sensitivity of screening for ovarian cancer using a Bayesian framework.
  3. Understanding the Landscape of Multi-Cancer Detection Tests: The Current Data and Clinical Considerations.
  4. Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations.
  5. Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology.
  6. Spatial omics technologies for understanding molecular status associated with cancer progression.
  7. TP53 mutations in urothelial carcinoma: not all one and the same†.
  8. The breast cancer tumor microenvironment and precision medicine: immunogenicity and conditions favoring response to immunotherapy.
  9. Detecting HRD in whole-genome and whole-exome sequenced breast and ovarian cancers.
  10. The epitranscriptome: reshaping the DNA damage response.
  11. Confirmation of large BRCA2 reversion deletions leading to reconstituted in-frame transcripts detected via circulating tumor DNA.
  12. Three Cases of Serous Tubal Intraepithelial Lesions (STILs).
  1. Nat Rev Clin Oncol. 2024 Jul 23.
    Spatial landscapes of cancers: insights and opportunities.
    Julia Chen, Ludvig Larsson, Alexander Swarbrick, Joakim Lundeberg.
      Solid tumours comprise many different cell types organized in spatially structured arrangements, with substantial intratumour and intertumour heterogeneity. Advances in spatial profiling technologies over the past decade hold promise to capture the complexity of these cellular architectures to build a holistic view of the intricate molecular mechanisms that shape the tumour ecosystem. Some of these mechanisms act at the cellular scale and are controlled by cell-autonomous programmes or communication between nearby cells, whereas other mechanisms result from coordinated efforts between large networks of cells and extracellular molecules organized into tissues and organs. In this Review we provide insights into the application of single-cell and spatial profiling tools, with a focus on spatially resolved transcriptomic tools developed to understand the cellular architecture of the tumour microenvironment and identify opportunities to use them to improve clinical management of cancers.
    DOI:  https://doi.org/10.1038/s41571-024-00926-7
  2. J Natl Cancer Inst. 2024 Jul 23. pii: djae145. [Epub ahead of print]
    Estimating sojourn time and sensitivity of screening for ovarian cancer using a Bayesian framework.
    Sayaka Ishizawa, Jiangong Niu, Martin C Tammemagi, Ehsan Irajizad, Yu Shen, Karen H Lu, Larissa A Meyer, Iakovos Toumazis.
       BACKGROUND: Ovarian cancer is among the leading causes of gynecologic cancer-related death. Past ovarian cancer screening trials using combination of cancer antigen 125 testing and transvaginal ultrasound failed to yield statistically significant mortality reduction. Estimates of ovarian cancer sojourn time-that is, the period from when the cancer is first screen detectable until clinical detection-may inform future screening programs.
    METHODS: We modeled ovarian cancer progression as a continuous time Markov chain and estimated screening modality-specific sojourn time and sensitivity using a Bayesian approach. Model inputs were derived from the screening arms (multimodal and ultrasound) of the UK Collaborative Trial of Ovarian Cancer Screening and the Prostate, Lung, Colorectal and Ovarian cancer screening trials. We assessed the quality of our estimates by using the posterior predictive P value. We derived histology-specific sojourn times by adjusting the overall sojourn time based on the corresponding histology-specific survival from the Surveillance, Epidemiology, and End Results Program.
    RESULTS: The overall ovarian cancer sojourn time was 2.1 years (posterior predictive P value = .469) in the Prostate, Lung, Colorectal and Ovarian studies, with 65.7% screening sensitivity. The sojourn time was 2.0 years (posterior predictive P value = .532) in the United Kingdom Collaborative Trial of Ovarian Cancer Screening's multimodal screening arm and 2.4 years (posterior predictive P value = .640) in the ultrasound screening arm, with sensitivities of 93.2% and 64.5%, respectively. Stage-specific screening sensitivities in the Prostate, Lung, Colorectal and Ovarian studies were 39.1% and 82.9% for early-stage and advanced-stage disease, respectively. The histology-specific sojourn times ranged from 0.8 to 1.8 years for type II ovarian cancer and 2.9 to 6.6 years for type I ovarian cancer.
    CONCLUSIONS: Annual screening is not effective for all ovarian cancer subtypes. Screening sensitivity for early-stage ovarian cancers is not sufficient for substantial mortality reduction.
    DOI:  https://doi.org/10.1093/jnci/djae145
  3. Life (Basel). 2024 Jul 19. pii: 896. [Epub ahead of print]14(7):
    Understanding the Landscape of Multi-Cancer Detection Tests: The Current Data and Clinical Considerations.
    Cody E Cotner, Elizabeth O'Donnell.
      Multi-cancer detection (MCD) tests are blood-based assays that screen for multiple cancers concurrently and offer a promising approach to improve early cancer detection and screening uptake. To date, there have been two prospective interventional studies evaluating MCD tests as a screening tool in human subjects. No MCD tests are currently approved by the FDA, but there is one commercially available MCD test. Ongoing trials continue to assess the efficacy, safety, and cost implications of MCD tests. In this review, we discuss the performance of CancerSEEK and Galleri, two leading MCD platforms, and discuss the clinical consideration for the broader application of this new technology.
    Keywords:  CancerSeek; Galleri; cancer screening; multi-cancer detection tests
    DOI:  https://doi.org/10.3390/life14070896
  4. Nat Commun. 2024 Jul 20. 15(1): 6139
    Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations.
    Elizaveta Besedina, Fran Supek.
      Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations.
    DOI:  https://doi.org/10.1038/s41467-024-50552-1
  5. Curr Issues Mol Biol. 2024 Jun 27. 46(7): 6533-6565
    Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology.
    Wan Ying Tan, Snigdha Nagabhyrava, Olivia Ang-Olson, Paromita Das, Luisa Ladel, Bethsebie Sailo, Linda He, Anup Sharma, Nita Ahuja.
      Technological advancements in cell-free DNA (cfDNA) liquid biopsy have triggered exponential growth in numerous clinical applications. While cfDNA-based liquid biopsy has made significant strides in personalizing cancer treatment, the exploration and translation of epigenetics in liquid biopsy to clinical practice is still nascent. This comprehensive review seeks to provide a broad yet in-depth narrative of the present status of epigenetics in cfDNA liquid biopsy and its associated challenges. It highlights the potential of epigenetics in cfDNA liquid biopsy technologies with the hopes of enhancing its clinical translation. The momentum of cfDNA liquid biopsy technologies in recent years has propelled epigenetics to the forefront of molecular biology. We have only begun to reveal the true potential of epigenetics in both our understanding of disease and leveraging epigenetics in the diagnostic and therapeutic domains. Recent clinical applications of epigenetics-based cfDNA liquid biopsy revolve around DNA methylation in screening and early cancer detection, leading to the development of multi-cancer early detection tests and the capability to pinpoint tissues of origin. The clinical application of epigenetics in cfDNA liquid biopsy in minimal residual disease, monitoring, and surveillance are at their initial stages. A notable advancement in fragmentation patterns analysis has created a new avenue for epigenetic biomarkers. However, the widespread application of cfDNA liquid biopsy has many challenges, including biomarker sensitivity, specificity, logistics including infrastructure and personnel, data processing, handling, results interpretation, accessibility, and cost effectiveness. Exploring and translating epigenetics in cfDNA liquid biopsy technology can transform our understanding and perception of cancer prevention and management. cfDNA liquid biopsy has great potential in precision oncology to revolutionize conventional ways of early cancer detection, monitoring residual disease, treatment response, surveillance, and drug development. Adapting the implementation of liquid biopsy workflow to the local policy worldwide and developing point-of-care testing holds great potential to overcome global cancer disparity and improve cancer outcomes.
    Keywords:  DNA methylation; cancer disparity; cancer screening; cell-free DNA; chromatin remodeling; circulating tumor DNA; early cancer detection; epigenetic drugs; epigenetics; epigenomics; fragmentomics; histone modification; liquid biopsy; nucleosome positioning; personalized medicine; precision oncology; targeted therapy; translational medicine
    DOI:  https://doi.org/10.3390/cimb46070390
  6. Cancer Sci. 2024 Jul 23.
    Spatial omics technologies for understanding molecular status associated with cancer progression.
    Satoi Nagasawa, Junko Zenkoh, Yutaka Suzuki, Ayako Suzuki.
      Cancer cells are generally exposed to numerous extrinsic stimulations in the tumor microenvironment. In this environment, cancer cells change their expression profiles to fight against circumstantial stresses, allowing their progression in the challenging tissue space. Technological advancements of spatial omics have had substantial influence on cancer genomics. This technical progress, especially that occurring in the spatial transcriptome, has been drastic and rapid. Here, we describe the latest spatial analytical technologies that have allowed omics feature characterization to retain their spatial and histopathological information in cancer tissues. Several spatial omics platforms have been launched, and the latest platforms finally attained single-cell level or even higher subcellular level resolution. We discuss several key papers elucidating the initial utility of the spatial analysis. In fact, spatial transcriptome analyses reveal comprehensive omics characteristics not only in cancer cells but also their surrounding cells, such as tumor infiltrating immune cells and cancer-associated fibroblasts. We also introduce several spatial omics platforms. We describe our own attempts to investigate molecular events associated with cancer progression. Furthermore, we discuss the next challenges in analyzing the multiomics status of cells, including their morphology and location. These novel technologies, in conjunction with spatial transcriptome analysis and, more importantly, with histopathology, will elucidate even novel key aspects of the intratumor heterogeneity of cancers. Such enhanced knowledge is expected to open a new path for overcoming therapeutic resistance and eventually to precisely stratify patients.
    Keywords:  cancer progression; multiomics; single‐cell resolution; spatial transcriptome; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.16283
  7. J Pathol. 2024 Jul 24.
    TP53 mutations in urothelial carcinoma: not all one and the same†.
    Alexis R Barr, Amy Burley, Anna Wilkins.
      Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, et al reports that disruptive versus non-disruptive TP53 mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive TP53 tumour mutations had poor overall survival versus those with non-disruptive TP53 mutations or wild type TP53 but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8+ T-cell infiltration was seen in tumours with disruptive mutations. The impact of different TP53 mutations on prognosis and therapy choices appears to be tumour- and therapy-type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of TP53 mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of TP53 mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of TP53 mutations on other clinically important aspects of the tumour microenvironment, including cancer-associated fibroblasts. Furthermore, the impact of gain-of-function mutations in TP53 and other related genes signalling upstream or downstream of TP53 is of wide interest. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  TP53 mutation; disruptive; immunotherapy; non‐disruptive; tumour microenvironment; urothelial carcinoma
    DOI:  https://doi.org/10.1002/path.6335
  8. J Natl Cancer Cent. 2024 Mar;4(1): 14-24
    The breast cancer tumor microenvironment and precision medicine: immunogenicity and conditions favoring response to immunotherapy.
    Andrea Nicolini, Paola Ferrari, Roberto Silvestri, Federica Gemignani.
      Some main recent researches that have dissected tumor microenvironment (TME) by imaging mass cytometry (IMC) in different subtypes of primary breast cancer samples were considered. The many phenotypic variants, clusters of epithelial tumor and immune cells, their structural features as well as the main genetic aberrations, sub-clonal heterogeneity and their systematic classification also have been examined. Mutational evolution has been assessed in primary and metastatic breast cancer samples. Overall, based on these findings the current concept of precision medicine is questioned and challenged by alternative therapeutic strategies. In the last two decades, immunotherapy as a powerful and harmless tool to fight cancer has received huge attention. Thus, the tumor immune microenvironment (TIME) composition, its prognostic role for clinical course as well as a novel definition of immunogenicity in breast cancer are proposed. Investigational clinical trials carried out by us and other findings suggest that G0-G1 state induced in endocrine-dependent metastatic breast cancer is more suitable for successful immune manipulation. Residual micro-metastatic disease seems to be another specific condition that can significantly favor the immune response in breast and other solid tumors.
    Keywords:  Breast cancer; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jncc.2024.01.004
  9. medRxiv. 2024 Jul 14. pii: 2024.07.14.24310383. [Epub ahead of print]
    Detecting HRD in whole-genome and whole-exome sequenced breast and ovarian cancers.
    Ammal Abbasi, Christopher D Steele, Erik N Bergstrom, Azhar Khandekar, Akanksha Farswan, Rana R Mckay, Nischalan Pillay, Ludmil B Alexandrov.
      Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1 , BRCA2 , and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational patterns due to the activities of HRD-associated mutational signatures. At least three machine learning tools exist for detecting HRD based on mutational patterns. Here, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. HRProfiler's performance is assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Our results demonstrate that HRProfiler is the only tool that robustly and consistently predicts clinical response from whole-exome sequenced breast and ovarian cancers.
    SIGNIFICANCE: HRProfiler is a novel machine learning approach that harnesses only six mutational features to detect clinically useful HRD from both whole-genome and whole-exome sequenced breast and ovarian cancers. Our results provide a practical way for detecting HRD and caution against using individual HRD-associated mutational signatures as clinical biomarkers.
    DOI:  https://doi.org/10.1101/2024.07.14.24310383
  10. Trends Cell Biol. 2024 Jul 23. pii: S0962-8924(24)00122-3. [Epub ahead of print]
    The epitranscriptome: reshaping the DNA damage response.
    Vivian Kalamara, George A Garinis.
      Genomic instability poses a formidable threat to cellular vitality and wellbeing, prompting cells to deploy an intricate DNA damage response (DDR) mechanism. Recent evidence has suggested that RNA is intricately linked to the DDR by serving as template, scaffold, or regulator during the repair of DNA damage. Additionally, RNA molecules undergo modifications, contributing to the epitranscriptome, a dynamic regulatory layer influencing cellular responses to genotoxic stress. The intricate interplay between RNA and the DDR sheds new light on how the RNA epigenome contributes to the maintenance of genomic integrity and ultimately shapes the fate of damaged cells.
    Keywords:  DNA damage response; DNA repair; RNA; epitranscriptome; m(6)A
    DOI:  https://doi.org/10.1016/j.tcb.2024.06.008
  11. Ann Oncol. 2024 Jul 22. pii: S0923-7534(24)01494-7. [Epub ahead of print]
    Confirmation of large BRCA2 reversion deletions leading to reconstituted in-frame transcripts detected via circulating tumor DNA.
    K A Collier, D G Stover.
      
    Keywords:  PARP inhibitors; breast cancer; drug resistance; homologous recombination deficiency; liquid biopsy; platinum
    DOI:  https://doi.org/10.1016/j.annonc.2024.07.720
  12. Cureus. 2024 Jun;16(6): e62895
    Three Cases of Serous Tubal Intraepithelial Lesions (STILs).
    Mika Mizuno, Shinichi Togami, Kyoko Shirota, Ikumi Kitazono, Hiroaki Kobayashi.
      Serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesions (STILs), and the p53 signature are considered to be related to precursor lesions of high-grade serous carcinomas (HGSCs). However, the clinical significance and prognostic implications of these lesion types are currently unknown. We diagnosed three patients with STILs according to the morphological evaluation criteria and combined this with p53 and Ki-67 immunostaining. One patient had an HGSC of the ovary that was incidentally discovered at the time of ovarian cyst resection, and the HGSC in the other two patients was characterized after they underwent risk-reducing salpingo-oophorectomy. Herein, we present a report of three patients with STILs diagnosed based on clinical data and pathological findings, along with a review of the literature.
    Keywords:  high-grade serous carcinomas; p53 signature; see-fim protocol; serous tubal intraepithelial carcinoma; serous tubal intraepithelial lesion
    DOI:  https://doi.org/10.7759/cureus.62895
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