bims-tumhet 2023-05-07 papers

Issue of 2023–05–07
six papers selected by
Sergio Marchini, Humanitas Research

Cancer Res. 2023 May 02. 83(9): 1383-1385

Understanding Long-Term Survival of Patients with Ovarian Cancer-The Tumor Microenvironment Comes to the Forefront.

High-grade serous ovarian cancer (HGSOC) is the deadliest subtype of ovarian cancer, and most patients do not survive more than 5 years after diagnosis. Yet, for reasons that are often elusive, approximately 15% of women with advanced-stage HGSOC will survive longer than 10 years. An understanding of the biological basis of long-term survival with HGSOC may elucidate novel prognostic factors and targets for treatment. Past analyses of the clinicopathologic features of these women and genetic profiles of their tumors have not revealed a unifying explanation for their increased longevity. In this issue of Cancer Research, Ferri-Borgogno and colleagues investigate the tumor microenvironment (TME) in samples from both long- and short-term survivors using spatial transcriptomics and single-cell RNA sequencing. They found that, in metastatic tumors, various populations of cancer-associated fibroblasts (CAF) in the TME play different roles in supporting the malignant phenotype of ovarian cancer cells. Higher density of CAFs, particularly αSMA+VIM+PDGFRβ+ CAFs, was associated with lower tumor immune infiltration and short-term survival. There was also marked expression of periostin and CD36 in spatially resolved CAFs, as well as a prevalence of the APOE-LRP5 ligand-receptor pair at the tumor-stromal interface in tissue from short-term survivors. These findings suggest that, in short-term survivors, CAFs are able to more effectively promote tumorigenicity, stemness, and chemoresistance in the nearby tumor. See related article by Ferri-Borgogno et al., p. 1503.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0333

PeerJ. 2023 ;11 e15244

CINmetrics: an R package for analyzing copy number aberrations as a measure of chromosomal instability.

Vishal H Oza, Jennifer L Fisher, Roshan Darji, Brittany N Lasseigne.

Genomic instability is an important hallmark of cancer and more recently has been identified in others like neurodegenrative diseases. Chromosomal instability, as a measure of genomic instability, has been used to characterize clinical and biological phenotypes associated with these diseases by measuring structural and numerical chromosomal alterations. There have been multiple chromosomal instability scores developed across many studies in the literature; however, these scores have not been compared because of the lack of a single tool available to calculate and facilitate these various metrics. Here, we provide an R package CINmetrics, that calculates six different chromosomal instability scores and allows direct comparison between them. We also demonstrate how these scores differ by applying CINmetrics to breast cancer data from The Cancer Genome Atlas (TCGA). The package is available on CRAN at https://cran.rproject.org/package=CINmetrics and on GitHub at https://github.com/lasseignelab/CINmetrics.

Keywords: CINmetrics; Cancer; Chromosomal instability; Copy number aberration; Genomic instability; R package

DOI: https://doi.org/10.7717/peerj.15244

Health Sci Rep. 2023 May;6(5): e1235

The role of DNA methylation in ovarian cancer chemoresistance: A narrative review.

Kaiyang Song, Mara Artibani.

Background and Aims: Ovarian cancer (OC) is the most lethal gynecological cancer. In 2018, it was responsible for over 180,000 deaths worldwide. The high mortality rate is the culmination of a lack of early diagnosis and high rates of chemotherapy resistance, which is synonymous with disease recurrence. Over the last two decades, an increasingly significant role of epigenetic mechanisms, in particular DNA methylation, has emerged. This review will discuss several of the most significant genes whose hypo/hypermethylation profiles are associated with chemoresistance. Aside from functionally elucidating and evaluating these epimutations, this review will discuss recent trials of DNA methyltransferase inhibitors (DNMTi). Finally, we will propose future directions that could enhance the feasibility of utilizing these candidate epimutations as clinical biomarkers.
Methods: To perform this review, a comprehensive literature search based on our keywords was conducted across the online databases PubMed and Google Scholar for identifying relevant studies published up until August 2022.
Results: Epimutations affecting MLH1, MSH2, and Ras-association domain family 1 isoform A (DNA damage repair and apoptosis); ATP-binding cassette subfamily B member 1 and methylation-controlled J (drug export); secreted frizzled-related proteins (Wnt/β-catenin signaling), neurocalcin delta (calcium and G protein-coupled receptor signaling), and zinc finger protein 671 all have potential as biomarkers for chemoresistance. However, specific uncertainties relating to these epimutations include histotype-specific differences, intrinsic versus acquired chemoresistance, and the interplay with complete surgical debulking. DNMTi for chemoresistant OC patients has shown some promise; however, issues surrounding their efficacy and dose-limiting toxicities remain; a personalized approach is required to maximize their effectiveness.
Conclusion: Establishing a panel of aberrantly methylated chemoresistance-related genes to predict chemoresponsiveness and patients' suitability to DNMTi could significantly reduce OC recurrence, while improving DNMTi therapy viability. To achieve this, a large-scale prospective genome-wide DNA methylation profile study that spans different histotypes, includes paired samples (before and after chemotherapy), and integrates transcriptomic and methylomic analysis, is warranted.

Keywords: chemoresistance; epigenetics; methylation; ovarian cancer

DOI: https://doi.org/10.1002/hsr2.1235

Cold Spring Harb Perspect Med. 2023 May 03. pii: a038216. [Epub ahead of print]

Prevention of Epithelial Ovarian Cancer.

Thomas A Sellers, Lauren C Peres, Cassandra A Hathaway, Shelley S Tworoger.

Given the challenges with achieving effective and durable treatment for epithelial ovarian cancer, primary prevention is highly desirable. Fortunately, decades of research have provided evidence for several strategies that can be deployed to optimize risk reduction. These include surgery, chemoprevention, and lifestyle factor modifications. These broad categories vary in terms of the magnitude of risk reduction possible, the possible short-term and long-term side effects, the degree of difficulty, and acceptability. Thus, the concept of a risk-based model to personalize preventive interventions is advocated to guide discussion between care providers and women at risk. For women with inherited major gene mutations that greatly increase risk of ovarian cancer, surgical approaches have favorable risk to benefit ratios. Chemoprevention and lifestyle factor modifications portend a lower degree of risk reduction but confer lower risk of undesirable side effects. Since complete prevention is not currently possible, better methods for early detection remain a high priority.

DOI: https://doi.org/10.1101/cshperspect.a038216

Mol Cell. 2023 Apr 24. pii: S1097-2765(23)00253-8. [Epub ahead of print]

PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools.

Morgan Dasovich, Anthony K L Leung.

PARPs catalyze ADP-ribosylation-a post-translational modification that plays crucial roles in biological processes, including DNA repair, transcription, immune regulation, and condensate formation. ADP-ribosylation can be added to a wide range of amino acids with varying lengths and chemical structures, making it a complex and diverse modification. Despite this complexity, significant progress has been made in developing chemical biology methods to analyze ADP-ribosylated molecules and their binding proteins on a proteome-wide scale. Additionally, high-throughput assays have been developed to measure the activity of enzymes that add or remove ADP-ribosylation, leading to the development of inhibitors and new avenues for therapy. Real-time monitoring of ADP-ribosylation dynamics can be achieved using genetically encoded reporters, and next-generation detection reagents have improved the precision of immunoassays for specific forms of ADP-ribosylation. Further development and refinement of these tools will continue to advance our understanding of the functions and mechanisms of ADP-ribosylation in health and disease.

Keywords: ADP-ribose biosensor; ADP-ribosylation; ADP-ribosylome; PAR-binding proteins; PARPs; chemical biology; drug development; proteomics

DOI: https://doi.org/10.1016/j.molcel.2023.04.009

Clin Cancer Res. 2023 May 02. pii: CCR-23-0250. [Epub ahead of print]

Monitoring sarcoma response to immune checkpoint inhibition and local cryotherapy with circulating tumor DNA analysis.

Nam Q Bui, Neda Nemat-Gorgani, Ajay Subramanian, Ileana A Torres, Marta Lohman, Timothy J Sears, Matt van de Rijn, Gregory W Charville, Hans-Christoph Becker, David S Wang, Gloria L Hwang, Kristen N Ganjoo, Everett J Moding.

PURPOSE: Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STSs), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STSs.
EXPERIMENTAL DESIGN: We enrolled 30 patients with unresectable or metastatic STS to a phase 2 clinical trial. Patients received ipilimumab and nivolumab for 4 doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle.
RESULTS: ctDNA was detected in at least one sample for 96% of patients. Pre-treatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pre-treatment to post-cryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed.
CONCLUSIONS: ctDNA represents a promising biomarker for monitoring response to treatment in advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STSs to immunotherapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-0250