bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024‒03‒17
six papers selected by
Sergio Marchini, Humanitas Research
  1. Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer.
  2. PARP Inhibitors: Strategic Use and Optimal Management in Ovarian Cancer.
  3. DNA methylation characteristics associated with chemotherapy resistance in epithelial ovarian cancer.
  4. AKTing on R Loops Makes for an ATRactive Target in Ovarian Cancer Therapy.
  5. Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.
  6. Assessing the New 2020 ESGO/ESTRO/ESP Endometrial Cancer Risk Molecular Categorization System for Predicting Survival and Recurrence.
  1. Eur J Cancer. 2024 Mar 02. pii: S0959-8049(24)00134-5. [Epub ahead of print]202 113978
    Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer.
    PAOLA-1/ ENGOT-ov25 Study Group
      BACKGROUND: The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status.METHODS: The study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS).
    RESULTS: We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with SeqOne assay and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68-1.42) and 1.05 (95% CI; 0.70-1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay.
    CONCLUSION: The SeqOne assay offers a clinically validated approach to detect HRD.
    Keywords:  BRCA; Genomic instability; Homologous recombination deficiency; Low-pass sequencing; Ovarian cancer; PARP-inhibitor; Whole genome sequencing
    DOI:  https://doi.org/10.1016/j.ejca.2024.113978
  2. Cancers (Basel). 2024 Feb 25. pii: 932. [Epub ahead of print]16(5):
    PARP Inhibitors: Strategic Use and Optimal Management in Ovarian Cancer.
    Nicholas Hirschl, Wildnese Leveque, Julia Granitto, Valia Sammarco, Mervyns Fontillas, Richard T Penson.
      Poly (ADP-ribose) polymerase (PARP) inhibitors have become an established part of the anticancer armamentarium. Discovered in the 1980s, PARP inhibitors (PARPis) were initially developed to exploit the presence of BRCA mutations, which disrupt the homologous recombination repair of deoxyribonucleic acid (DNA) via synthetic lethality, an intrinsic vulnerability caused by the cell's dependence on other DNA repair mechanisms for which PARP is an essential contributor. PARPi use expanded with the demonstration of clinical benefit when other mechanisms of high-fidelity DNA damage response were present in cancer cells called homologous repair deficiency (HRD). Recently, new data have resulted in the voluntary withdrawal of later-line treatment indications for all the available PARPis used in ovarian cancer because of a negative impact on overall survival (OS). PARPi switch maintenance to consolidate a response to platinum-based therapy is recommended for earlier treatment lines to have the greatest impact on the chance of cure and length of survival. This article reviews the clinical utility of PARPis and how to integrate them into best practices.
    Keywords:  gynecologic; niraparib; olaparib; oncology; rucaparib; targeted
    DOI:  https://doi.org/10.3390/cancers16050932
  3. Heliyon. 2024 Mar 15. 10(5): e27212
    DNA methylation characteristics associated with chemotherapy resistance in epithelial ovarian cancer.
    Changling Duan, Zhongxin Yan, Cailiang Wu, Xuexin Zhou, Wei Bao.
      Objective: The high mortality rate of epithelial ovarian cancer (EOC) is often attributed to the frequent development of chemoresistance. DNA methylation is a predictive biomarker for chemoresistance.Methods: This study utilized DNA methylation profiles and relevant information from GEO and TCGA to identify different methylated CpG sites (DMCs) between chemoresistant and chemosensitive patients. Subsequently, we constructed chemoresistance risk models with DMCs. The genes corresponding to candidate DMCs in chemoresistance risk models were further analyzed to identify different methylated gene symbols (DMGs) associated with chemoresistance. The DMGs that showed a strong correlation with the corresponding DMCs were analyzed through immunohistochemistry.
    Results: Compared to chemosensitive EOC patients, chemoresistant patients showed 423 hypermethylated CpGs and 1445 hypomethylated CpGs. The chemoresistance risk models based on DMCs have shown the improved predictive ability for chemoresistance in EOC (AUC = 65.0-76.2%). The methylations of cg25510164, cg13154880, cg15362155 and cg08665359 were strongly associated with decreased risk of chemoresistance. Conversely, the methylation of cg08872590 and cg14739437 significantly increased the risk. We identified 13 DMGs, from 47 DMCs corresponding genes, between chemosensitive and chemoresistant samples. Among the DMGs, the expression levels of DDR2 and OPCML exhibited strong correlations with the corresponding DMCs. DDR2 and OPCML both showed enhanced expression in chemoresistant ovarian microarray tissue.
    Conclusions: Hypomethylated CpGs may play a significant role in DNA methylation associated with chemoresistance in EOC. The epigenetic modification of DDR2 could have important implications for the development of chemoresistance. Our study provides valuable insights for future research on DNA methylation in the chemoresistance of EOC.
    Keywords:  Chemotherapy resistance; DDR2; Methylation; OPCML; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27212
  4. Cancer Res. 2024 Mar 15. 84(6): 793-795
    AKTing on R Loops Makes for an ATRactive Target in Ovarian Cancer Therapy.
    Vijayalalitha Ramanarayanan, Philipp Oberdoerffer.
      High-grade serous ovarian carcinoma (HGSOC) is the deadliest subtype of ovarian cancer. While PARP inhibitors (PARPi) have transformed the care of advanced HGSOC, PARPi resistance poses a major limitation to their clinical utility. DNA damage checkpoint signaling via ATR kinase can counteract PARPi-induced replication stress, making ATR an attractive therapeutic target in PARPi-resistant tumors. However, ATR inhibitor (ATRi) efficacy in the clinic is low, emphasizing the need for suitable combination treatments. In this issue of Cancer Research, Huang and colleagues uncovered cytotoxic synergism between inhibition of the PI3K/AKT pathway and ATR based on high-throughput screening for ATRi drug combinations in PARPi-resistant HGSOC cells. Dual inhibition of ATR and AKT resulted in aberrant replication stress and cell death, which was attributed in part to impaired resolution of replication-stalling RNA:DNA hybrids (R loops). The authors identified the DNA/RNA helicase DHX9 as a clinically relevant candidate effector of R loop resolution in HGSOC. AKT interacted with and recruited DHX9 to R loops, where it complemented ATR in facilitating their removal. Underlining the therapeutic potential relevance of these findings, combined inhibition of ATR and AKT caused near complete tumor regression in HGSOC xenograft models, and elevated AKT/DHX9 levels correlated with poor survival in patients with HGSOC. Of note, the genotoxic consequences of dual ATRi/AKTi treatment extended beyond PARPi-resistant tumors and are likely to affect genome integrity beyond R loops. The work by Huang and colleagues thus provides compelling rationale for the exploration of combined targeting of the AKT and ATR pathways as a potentially broadly applicable treatment of advanced HGSOC. See related article by Huang et al., p. 887.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-4129
  5. Nat Commun. 2024 Mar 12. 15(1): 2220
    Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.
    Kate E Stanley, Tatjana Jatsenko, Stefania Tuveri, Dhanya Sudhakaran, Lore Lannoo, Kristel Van Calsteren, Marie de Borre, Ilse Van Parijs, Leen Van Coillie, Kris Van Den Bogaert, Rodrigo De Almeida Toledo, Liesbeth Lenaerts, Sabine Tejpar, Kevin Punie, Laura Y Rengifo, Peter Vandenberghe, Bernard Thienpont, Joris Robert Vermeesch.
      Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.
    DOI:  https://doi.org/10.1038/s41467-024-46435-0
  6. Cancers (Basel). 2024 Feb 27. pii: 965. [Epub ahead of print]16(5):
    Assessing the New 2020 ESGO/ESTRO/ESP Endometrial Cancer Risk Molecular Categorization System for Predicting Survival and Recurrence.
    Yung-Taek Ouh, Yoonji Oh, Jinwon Joo, Joo Hyun Woo, Hye Jin Han, Hyun Woong Cho, Jae Kwan Lee, Yikyeong Chun, Myoung-Nam Lim, Jin Hwa Hong.
      This study aimed to evaluate the efficacy of the 2020 European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer (EC). Additionally, a novel risk category incorporating clinicopathological and molecular factors was introduced. The predictive value of this new category for recurrence and survival in Korean patients with EC was assessed, and comparisons were made with the 2013 and 2016 European Society of Medical Oncology (ESMO) risk classifications. Patients with EC were categorized into the POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-aberrant (P53abn), and nonspecific molecular profile (NSMP) subtypes. Recurrence, survival, and adjuvant therapy were assessed according to each classification. Notably, patients with the POLEmut subtype showed no relapse, while patients with the P53abn subtype exhibited higher recurrence (31.8%) and mortality rates (31.8%). Regarding adjuvant therapy, 33.3% of low-risk patients were overtreated according to the 2020 ESGO/ESTRO/ESP guidelines. Overall and progression-free survival differed significantly across molecular classifications, with the POLEmut subtype showing the best and the P53abn subtype showing the worst outcomes. The 2020 ESGO molecular classification system demonstrated practical utility and significantly influenced survival outcomes. Immunohistochemistry for TP53 and MMR, along with POLE sequencing, facilitated substantial patient reclassification, underscoring the clinical relevance of molecular risk categories in EC management.
    Keywords:  endometrial cancer; mismatch repair; molecular classification; p53; polymerase epsilon
    DOI:  https://doi.org/10.3390/cancers16050965
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒20 at 9:24.