bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–03–12
eleven papers selected by
Sergio Marchini, Humanitas Research
  1. New therapies for clear cell ovarian carcinoma.
  2. Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer.
  3. Review the progression of ovarian clear cell carcinoma from the perspective of genomics and epigenomics.
  4. Genomic testing in high-grade serous ovarian cancer: current options and future development.
  5. Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer.
  6. cGAS-STING signalling in cancer: striking a balance with chromosomal instability.
  7. Novel therapeutics in low-grade serous ovarian cancer.
  8. High-resolution alignment of single-cell and spatial transcriptomes with CytoSPACE.
  9. Characterization of Primary Mucinous Ovarian Cancer by Diffusion-Weighted and Dynamic Contrast Enhancement MRI in Comparison with Serous Ovarian Cancer.
  10. Validation of the new EPIC DNA methylation microarray (900K EPIC v2) for high-throughput profiling of the human DNA methylome.
  11. DNA Damage and Its Role in Cancer Therapeutics.
  1. Int J Gynecol Cancer. 2023 03 06. 33(3): 385-393
    New therapies for clear cell ovarian carcinoma.
    James Stewart, Niamh Cunningham, Susana Banerjee.
      Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.
    Keywords:  Ovarian Cancer
    DOI:  https://doi.org/10.1136/ijgc-2022-003704
  2. Ther Adv Med Oncol. 2023 ;15 17588359231157644
    Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer.
    Ana C Veneziani, Clare Scott, Matthew J Wakefield, Anna V Tinker, Stephanie Lheureux.
      Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a therapeutic milestone in the management of epithelial ovarian cancer. The concept of 'synthetic lethality' is exploited by PARPi in tumors with defects in DNA repair pathways, particularly homologous recombination deficiency. The use of PARPis has been increasing since its approval as maintenance therapy, particularly in the first-line setting. Therefore, resistance to PARPi is an emerging issue in clinical practice. It brings an urgent need to elucidate and identify the mechanisms of PARPi resistance. Ongoing studies address this challenge and investigate potential therapeutic strategies to prevent, overcome, or re-sensitize tumor cells to PARPi. This review aims to summarize the mechanisms of resistance to PARPi, discuss emerging strategies to treat patients post-PARPi progression, and discuss potential biomarkers of resistance.
    Keywords:  PARP inhibitor; biomarkers; homologous recombination deficiency; ovarian cancer; replication stress
    DOI:  https://doi.org/10.1177/17588359231157644
  3. Front Genet. 2023 ;14 952379
    Review the progression of ovarian clear cell carcinoma from the perspective of genomics and epigenomics.
    An Tong, Xiangjie Di, Xia Zhao, Xiao Liang.
      Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer with unique molecular characteristics, specific biological and clinical behavior, poor prognosis and high resistance to chemotherapy. Pushed by the development of genome-wide technologies, our knowledge about the molecular features of OCCC has been considerably advanced. Numerous studies are emerging as groundbreaking, and many of them are promising treatment strategies. In this article, we reviewed studies about the genomics and epigenetics of OCCC, including gene mutation, copy number variations, DNA methylation and histone modifications.
    Keywords:  epigenomics; genomics; gynecological oncology; ovarian clear cell carcinoma; review
    DOI:  https://doi.org/10.3389/fgene.2023.952379
  4. Int J Gynecol Cancer. 2023 03 06. 33(3): 358-363
    Genomic testing in high-grade serous ovarian cancer: current options and future development.
    Michael-John Devlin, Rowan Miller.
      Understanding the genomic complexity of high-grade serous ovarian cancer is now essential in guiding patient management, particularly in the first-line setting. Our knowledge in this area has expanded rapidly in recent years, with biomarkers developing in parallel to agents designed to exploit cancer-associated genetic aberrations. In this review we will take stock of the current landscape of genetic testing and look towards the future with developments that aim to refine personalized treatment paradigms and track treatment resistance in real time.
    Keywords:  Cystadenocarcinoma, Serous; Medical Oncology; Ovary
    DOI:  https://doi.org/10.1136/ijgc-2022-003702
  5. Int J Cancer. 2023 Mar 08.
    Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer.
    Romina Silva, Kate Glennon, Michael Metoudi, Bruce Moran, Sofia Salta, Karen Slattery, Ann Treacy, Terri Martin, Jacqui Shaw, Peter Doran, Lydia Lynch, Carmen Jeronimo, Antoinette S Perry, Donal J Brennan.
      Resistance to platinum-based chemotherapy is the major cause of death from high-grade serous ovarian cancer (HGSOC). We hypothesize that detection of specific DNA methylation changes may predict platinum resistance in HGSOC. Using a publicly available "discovery" dataset we examined epigenomic and transcriptomic alterations between primary platinum-sensitive (n = 32) and recurrent acquired drug resistant HGSOC (n = 28) and identified several genes involved in immune and chemoresistance-related pathways. Validation via high-resolution melt analysis of these findings, in cell lines and HGSOC tumours, demonstrated the most consistent changes were observed in three of the genes: APOBEC3A, NKAPL and PDCD1. Plasma samples from an independent HGSOC cohort (n = 17) were analysed using droplet digital PCR. Hypermethylation of NKAPL was detected in 46% and hypomethylation of APOBEC3A in 69% of plasma samples taken from women with relapsed HGSOC (n = 13), with no alterations identified in disease-free patients (n = 4). Following these results, and using a CRISPR-Cas9 approach, we were also able to demonstrate that in vitro NKAPL promoter demethylation increased platinum sensitivity by 15%. Overall, this study demonstrates the importance of aberrant methylation, especially of the NKAPL gene, in acquired platinum resistance in HGSOC. This article is protected by copyright. All rights reserved.
    Keywords:  DNA methylation; acquired drug resistance; high-grade serous ovarian cancer; liquid biopsy; targeted epigenetic editing
    DOI:  https://doi.org/10.1002/ijc.34496
  6. Biochem Soc Trans. 2023 Mar 06. pii: BST20220838. [Epub ahead of print]
    cGAS-STING signalling in cancer: striking a balance with chromosomal instability.
    Bruno Beernaert, Eileen E Parkes.
      Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are detected by the nucleic acid sensor cGAS, leading to the production of the second messenger 2'3'-cGAMP and activation of the critical hub of innate immune signalling STING. Activation of this immune pathway should instigate the influx and activation of immune cells, resulting in the eradication of cancer cells. That this does not universally occur in the context of CIN remains an unanswered paradox in cancer. Instead, CIN-high cancers are notably adept at immune evasion and are highly metastatic with typically poor outcomes. In this review, we discuss the diverse facets of the cGAS-STING signalling pathway, including emerging roles in homeostatic processes and their intersection with genome stability regulation, its role as a driver of chronic pro-tumour inflammation, and crosstalk with the tumour microenvironment, which may collectively underlie its apparent maintenance in cancers. A better understanding of the mechanisms whereby this immune surveillance pathway is commandeered by chromosomally unstable cancers is critical to the identification of new vulnerabilities for therapeutic exploitation.
    Keywords:  DNA synthesis and repair; cGAS-STING; chromosomal instability; immunosurveillance; innate immunity
    DOI:  https://doi.org/10.1042/BST20220838
  7. Int J Gynecol Cancer. 2023 03 06. 33(3): 377-384
    Novel therapeutics in low-grade serous ovarian cancer.
    Lauren Cobb, David Gershenson.
      Low-grade serous ovarian cancer is a rare subtype of epithelial ovarian cancer clinically characterized by younger age at diagnosis, relative chemoresistance, and prolonged survival compared with its high-grade serous counterpart. It is molecularly characterized by estrogen and progesterone receptor positivity, aberrations in the MAPK (mitogen-activated protein kinase) pathway, and wild-type TP53 expression pattern. As research into low-grade serous ovarian cancer as a distinct entity has been able to accelerate independently, we have learned more about its unique pathogenesis, oncogenic drivers, and opportunities for novel therapeutics. In the primary setting, cytoreductive surgery in combination with platinum-based chemotherapy remain the standard of care. However, low-grade serous ovarian cancer has demonstrated relative chemoresistance in the primary and recurrent settings. Endocrine therapy is also commonly utilized in the maintenance and recurrent settings and is being evaluated in the adjuvant setting. Given the many similarities of low-grade serous ovarian cancer to luminal breast cancer, many recent studies have utilized similar therapeutic strategies including endocrine therapy combinations with CDK (cyclin-dependent kinase) 4/6 inhibitors. Additionally, recent trials have investigated combination therapies targeting the MAPK pathway, including MEK (mitogen-activated protein kinase kinase), BRAF (v-raf murine sarcoma viral oncogene homolog B1), FAK (focal adhesion kinase), and PI3K (phosphatidylinositol 3-kinase) inhibition. In this review, we will outline these novel therapeutic strategies for low-grade serous ovarian cancer.
    Keywords:  Cystadenocarcinoma, Serous; Gynecology; Ovarian Cancer
    DOI:  https://doi.org/10.1136/ijgc-2022-003677
  8. Nat Biotechnol. 2023 Mar 06.
    High-resolution alignment of single-cell and spatial transcriptomes with CytoSPACE.
    Milad R Vahid, Erin L Brown, Chloé B Steen, Wubing Zhang, Hyun Soo Jeon, Minji Kang, Andrew J Gentles, Aaron M Newman.
      Recent studies have emphasized the importance of single-cell spatial biology, yet available assays for spatial transcriptomics have limited gene recovery or low spatial resolution. Here we introduce CytoSPACE, an optimization method for mapping individual cells from a single-cell RNA sequencing atlas to spatial expression profiles. Across diverse platforms and tissue types, we show that CytoSPACE outperforms previous methods with respect to noise tolerance and accuracy, enabling tissue cartography at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41587-023-01697-9
  9. Cancers (Basel). 2023 Feb 24. pii: 1453. [Epub ahead of print]15(5):
    Characterization of Primary Mucinous Ovarian Cancer by Diffusion-Weighted and Dynamic Contrast Enhancement MRI in Comparison with Serous Ovarian Cancer.
    Laretta Grabowska-Derlatka, Pawel Derlatka, Marta Hałaburda-Rola.
      (1) Background. The purpose of this study is to evaluate the diagnostic accuracy of a quantitative analysis of diffusion-weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI of mucinous ovarian cancer (MOC). It also aims to differentiate between low grade serous carcinoma (LGSC), high-grade serous carcinoma (HGSC) and MOC in primary tumors. (2) Materials and Methods. Sixty-six patients with histologically confirmed primary epithelial ovarian cancer (EOC) were included in the study. Patients were divided into three groups: MOC, LGSC and HGSC. In the preoperative DWI and DCE MRI, selected parameters were measured: apparent diffusion coefficients (ADC), time to peak (TTP), and perfusion maximum enhancement (Perf. Max. En.). ROI comprised a small circle placed in the solid part of the primary tumor. The Shapiro-Wilk test was used to test whether the variable had a normal distribution. The Kruskal-Wallis ANOVA test was used to determine the p-value needed to compare the median values of interval variables. (3) Results. The highest median ADC values were found in MOC, followed by LGSC, and the lowest in HGSC. All differences were statistically significant (p < 0.000001). This was also confirmed by the ROC curve analysis for MOC and HGSC, showing that ADC had excellent diagnostic accuracy in differentiating between MOC and HGSC (p < 0.001). In the type I EOCs, i.e., MOC and LGSC, ADC has less differential value (p = 0.032), and TTP can be considered the most valuable parameter for diagnostic accuracy (p < 0.001). (4) Conclusions. DWI and DCE appear to be very good diagnostic tools in differentiating between serous carcinomas (LGSC, HGSC) and MOC. Significant differences in median ADC values between MOC and LGSC compared with those between MOC and HGSC indicate the usefulness of DWI in differentiating between less and more aggressive types of EOC, not only among the most common serous carcinomas. ROC curve analysis showed that ADC had excellent diagnostic accuracy in differentiating between MOC and HGSC. In contrast, TTP showed the greatest value for differentiating between LGSC and MOC.
    Keywords:  high-grade serous ovarian cancer (HGSC); low-grade serous ovarian cancer (LGSC); magnetic resonance diffusion-weighted imaging (DWI); magnetic resonance dynamic contrast enhancement (DCE); mucinous ovarian cancer (MOC)
    DOI:  https://doi.org/10.3390/cancers15051453
  10. Epigenetics. 2023 Dec;18(1): 2185742
    Validation of the new EPIC DNA methylation microarray (900K EPIC v2) for high-throughput profiling of the human DNA methylome.
    Aleix Noguera-Castells, Carlos A García-Prieto, Damiana Álvarez-Errico, Manel Esteller.
      DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes in humans. On top of that, the DNA methylome undergoes profound changes in cancer and other disorders. However, large-scale and population-based studies are limited by high costs and the need for considerable expertise in data analysis for whole-genome bisulphite-sequencing methodologies. Following the success of the EPIC DNA methylation microarray, the newly developed Infinium HumanMethylationEPIC version 2.0 (900K EPIC v2) is now available. This new array contains more than 900,000 CpG probes covering the human genome and excluding masked probes from the previous version. The 900K EPIC v2 microarray adds more than 200,000 probes covering extra DNA cis-regulatory regions such as enhancers, super-enhancers and CTCF binding regions. Herein, we have technically and biologically validated the new methylation array to show its high reproducibility and consistency among technical replicates and with DNA extracted from FFPE tissue. In addition, we have hybridized primary normal and tumoural tissues and cancer cell lines from different sources and tested the robustness of the 900K EPIC v2 microarray when analysing the different DNA methylation profiles. The validation highlights the improvements offered by the new array and demonstrates the versatility of this updated tool for characterizing the DNA methylome in human health and disease.
    Keywords:  CpG sites; DNA methylation; Human; epigenetics; microarray; validation
    DOI:  https://doi.org/10.1080/15592294.2023.2185742
  11. Int J Mol Sci. 2023 Mar 01. pii: 4741. [Epub ahead of print]24(5):
    DNA Damage and Its Role in Cancer Therapeutics.
    Jaeyoung Moon, Ichiwa Kitty, Kusuma Renata, Sisi Qin, Fei Zhao, Wootae Kim.
      DNA damage is a double-edged sword in cancer cells. On the one hand, DNA damage exacerbates gene mutation frequency and cancer risk. Mutations in key DNA repair genes, such as breast cancer 1 (BRCA1) and/or breast cancer 2 (BRCA2), induce genomic instability and promote tumorigenesis. On the other hand, the induction of DNA damage using chemical reagents or radiation kills cancer cells effectively. Cancer-burdening mutations in key DNA repair-related genes imply relatively high sensitivity to chemotherapy or radiotherapy because of reduced DNA repair efficiency. Therefore, designing specific inhibitors targeting key enzymes in the DNA repair pathway is an effective way to induce synthetic lethality with chemotherapy or radiotherapy in cancer therapeutics. This study reviews the general pathways involved in DNA repair in cancer cells and the potential proteins that could be targeted for cancer therapeutics.
    Keywords:  DNA damage; cancer therapeutics; mutations
    DOI:  https://doi.org/10.3390/ijms24054741
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