bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–12–10
nine papers selected by
Sergio Marchini, Humanitas Research
  1. Potential cGAS-STING pathway functions in DNA damage responses, DNA replication and DNA repair.
  2. Spatially resolved multiomics.
  3. Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping.
  4. Aneuploidy Landscape in Precursors of Ovarian Cancer.
  5. Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.
  6. Cancer Evolution: A Multifaceted Affair.
  7. The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
  8. Circulating tumor DNA enables sensitive detection of actionable gene fusions and rearrangements across cancer types.
  9. False-Positive Liquid Biopsy Assays Secondary to Overlapping Aberrant Methylation from Non-Cancer Disease States.
  1. DNA Repair (Amst). 2023 Nov 30. pii: S1568-7864(23)00162-3. [Epub ahead of print]133 103608
    Potential cGAS-STING pathway functions in DNA damage responses, DNA replication and DNA repair.
    Christian Zierhut.
      The major innate immune responder to the DNA of pathogens is the cyclic GMP-AMP (cGAMP) synthase (cGAS) - stimulator of interferon genes (STING) pathway. Most prominently, the outcome of cGAS signalling is the activation of inflammatory transcription through interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB). In addition, the cGAS-STING pathway can lead to the direct modulation of cellular processes independently of transcription, such as activation of autophagy. Under unperturbed conditions, several mechanisms are in place to prevent the activation of cGAS by self-DNA, chiefly its sequestration on chromatin, which interferes with binding to stimulatory DNA. However, under conditions of genotoxic stress and chromosomal instability, this inhibition breaks down, resulting in the activation of cGAS, which drives sterile inflammation, as well as cell fate and immune responses in cancer. Recently, several studies have suggested that cGAS, STING, or downstream pathway components can also regulate the DNA damage response, DNA damage checkpoint signalling, DNA repair and DNA replication. Here, I review these proposed mechanisms, and discuss some unanswered questions relating to them.
    Keywords:  CGAS-STING; DNA damage checkpoints, DNA repair; DNA replication; Innate immunity
    DOI:  https://doi.org/10.1016/j.dnarep.2023.103608
  2. Nat Methods. 2023 Dec 06.
    Spatially resolved multiomics.
    Lei Tang.
      
    DOI:  https://doi.org/10.1038/s41592-023-02110-8
  3. Nat Med. 2023 Dec 04.
    Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping.
    Sylvan C Baca, Ji-Heui Seo, Matthew P Davidsohn, Brad Fortunato, Karl Semaan, Shahabbedin Sotudian, Gitanjali Lakshminarayanan, Miklos Diossy, Xintao Qiu, Talal El Zarif, Hunter Savignano, John Canniff, Ikenna Madueke, Renee Maria Saliby, Ziwei Zhang, Rong Li, Yijia Jiang, Len Taing, Mark Awad, Cindy H Chau, James A DeCaprio, William D Figg, Tim F Greten, Aaron N Hata, F Stephen Hodi, Melissa E Hughes, Keith L Ligon, Nancy Lin, Kimmie Ng, Matthew G Oser, Catherine Meador, Heather A Parsons, Mark M Pomerantz, Arun Rajan, Jerome Ritz, Manisha Thakuria, Sara M Tolaney, Patrick Y Wen, Henry Long, Jacob E Berchuck, Zoltan Szallasi, Toni K Choueiri, Matthew L Freedman.
      
    DOI:  https://doi.org/10.1038/s41591-023-02735-4
  4. Clin Cancer Res. 2023 Dec 01.
    Aneuploidy Landscape in Precursors of Ovarian Cancer.
    Yeh Wang, Christopher Douville, Yen-Wei Chien, Brant G Wang, Chi-Long Chen, Andre Pinto, Saron Ann Smith, Ronny Drapkin, M Herman Chui, Tricia Numan, Russell Vang, Nickolas Papadopoulos, Tian-Li Wang, Ie-Ming Shih.
       PURPOSE: Serous tubal intraepithelial carcinoma(STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma(HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression.
    EXPERIMENTAL DESIGN: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC(cases, n=85), and histologically unremarkable fallopian tube epithelium(HU-FTE, control, n=65). Based on a discovery set(n=67), we developed an aneuploidy-based algorithm, REAL-FAST, to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set(n=83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology.
    RESULTS: We found nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12(CCNE1), 19q13.2, 8q24(MYC), or 8q arm, while proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. Based on a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC.
    CONCLUSIONS: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STICs.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0932
  5. Sci Transl Med. 2023 Dec 06. 15(725): eadi2556
    Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.
    TOWARDS group
      Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.
    DOI:  https://doi.org/10.1126/scitranslmed.adi2556
  6. Cancer Discov. 2023 Dec 06. OF1-OF13
    Cancer Evolution: A Multifaceted Affair.
    Giovanni Ciriello, Luca Magnani, Sarah J Aitken, Leila Akkari, Sam Behjati, Douglas Hanahan, Dan A Landau, Nuria Lopez-Bigas, Darío G Lupiáñez, Jean-Christophe Marine, Ana Martin-Villalba, Gioacchino Natoli, Anna C Obenauf, Elisa Oricchio, Paola Scaffidi, Andrea Sottoriva, Alexander Swarbrick, Giovanni Tonon, Sakari Vanharanta, Johannes Zuber.
      Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery.
    SIGNIFICANCE: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0530
  7. Nat Genet. 2023 Dec 04.
    The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
    Deborah R Caswell, Philippe Gui, Manasi K Mayekar, Emily K Law, Oriol Pich, Chris Bailey, Jesse Boumelha, D Lucas Kerr, Collin M Blakely, Tadashi Manabe, Carlos Martinez-Ruiz, Bjorn Bakker, Juan De Dios Palomino Villcas, Natalie I Vokes, Michelle Dietzen, Mihaela Angelova, Beatrice Gini, Whitney Tamaki, Paul Allegakoen, Wei Wu, Timothy J Humpton, William Hill, Mona Tomaschko, Wei-Ting Lu, Franziska Haderk, Maise Al Bakir, Ai Nagano, Francisco Gimeno-Valiente, Sophie de Carné Trécesson, Roberto Vendramin, Vittorio Barbè, Miriam Mugabo, Clare E Weeden, Andrew Rowan, Caroline E McCoach, Bruna Almeida, Mary Green, Carlos Gomez, Shigeki Nanjo, Dora Barbosa, Chris Moore, Joanna Przewrocka, James R M Black, Eva Grönroos, Alejandro Suarez-Bonnet, Simon L Priestnall, Caroline Zverev, Scott Lighterness, James Cormack, Victor Olivas, Lauren Cech, Trisha Andrews, Brandon Rule, Yuwei Jiao, Xinzhu Zhang, Paul Ashford, Cameron Durfee, Subramanian Venkatesan, Nuri Alpay Temiz, Lisa Tan, Lindsay K Larson, Prokopios P Argyris, William L Brown, Elizabeth A Yu, Julia K Rotow, Udayan Guha, Nitin Roper, Johnny Yu, Rachel I Vogel, Nicholas J Thomas, Antonio Marra, Pier Selenica, Helena Yu, Samuel F Bakhoum, Su Kit Chew, Jorge S Reis-Filho, Mariam Jamal-Hanjani, Karen H Vousden, Nicholas McGranahan, Eliezer M Van Allen, Nnennaya Kanu, Reuben S Harris, Julian Downward, Trever G Bivona, Charles Swanton.
      In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.
    DOI:  https://doi.org/10.1038/s41588-023-01592-8
  8. Clin Cancer Res. 2023 Dec 07.
    Circulating tumor DNA enables sensitive detection of actionable gene fusions and rearrangements across cancer types.
    Pashtoon M Kasi, Jessica K Lee, Lincoln W Pasquina, Brennan Decker, Pierre Vanden Borre, Dean C Pavlick, Justin M Allen, Christine Parachoniak, Julia C F Quintanilha, Ryon P Graf, Alexa B Schrock, Geoffrey R Oxnard, Christine M Lovly, Hanna Tukachinsky, Vivek Subbiah.
       PURPOSE: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types.
    MATERIALS AND METHODS: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOne®Liquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes. Tissue biopsies (TBx) profiled using FoundationOne®CDx were used as a comparator.
    RESULTS: Among all LBx, 7,377 (14%) had ≥1 pathogenic rearrangement detected. 3,648 (6.8%) LBx had ≥1 gain-of-function (GOF) oncogene rearrangement, and 4,428 (8.2%) LBx had ≥1 loss-of-function rearrangement detected. Cancer types with higher prevalence of GOF rearrangements included those with canonical fusion drivers: prostate cancer (19%), cholangiocarcinoma (6.4%), bladder (5.5%), and non-small cell lung cancer (4.4%). Although the prevalence of driver rearrangements was lower in LBx than TBx overall, the frequency of detection was comparable in LBx with a tumor fraction (TF) ≥1%. Rearrangements in FGFR2, BRAF, RET, and ALK, were detected across cancer types, but tended to be clonal variants in some cancer types and potential acquired resistance variants in others.
    CONCLUSIONS: In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2693
  9. Case Rep Oncol. 2023 Jan-Dec;16(1):16(1): 1536-1541
    False-Positive Liquid Biopsy Assays Secondary to Overlapping Aberrant Methylation from Non-Cancer Disease States.
    Areeb Lutfi, Maaz Khan Afghan, Brandon Swed, Pashtoon Murtaza Kasi.
       Introduction: Liquid biopsies are increasingly being adopted in the care of patients with cancer. Not only in patients with metastatic disease but the utility is also being recognized in earlier phases of the journey of a patient with cancer. More recently, methylated platforms are offering another lens of looking at the same question more so in minimal residual disease (MRD) and early detection settings. While false positives secondary to clonal hematopoiesis of indeterminate potential (CHIP) are recognized as one entity to consider when interpreting these assays, and advanced CHIP filtering bioinformatics platforms can prevent this, false positives secondary to aberrant methylation are not described.
    Case Presentation: Herein, we report a case of a patient with hepatitis C-related viremia and a very high viral load that had a false-positive plasma-only colorectal MRD assay. The colorectal MRD assay spontaneously cleared on hepatitis C virus therapy which led to clearance of the virus.
    Conclusion: As these assays are increasingly applied in real-world settings, it would be of value to consider non-cancer chronic disease states that may lead to aberrant methylation that could lead to a false-positive assay.
    Keywords:  Circulating tumor DNA; Colorectal cancer; False positive; Hepatitis C virus; Liquid biopsy; Methylation
    DOI:  https://doi.org/10.1159/000535174
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