bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2023–01–15
eleven papers selected by
Lara Paracchini, Humanitas Research
  1. Identification of TP53 mutations in circulating tumour DNA in high grade serous ovarian carcinoma using next generation sequencing technologies.
  2. Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse.
  3. Prophylactic Salpingectomy during Hysterectomy for Benign Disease: A Prospective Study to Evaluate High-Grade Serous Ovarian Carcinoma Precursors.
  4. Diagnostic and prognostic potential of the microbiome in ovarian cancer treatment response.
  5. Genome-wide analysis of aberrant position and sequence of plasma DNA fragment ends in patients with cancer.
  6. Parts-based decomposition of spatial genomics data finds distinct tissue regions.
  7. Genetics of clonal hematopoiesis.
  8. Efficacy and safety of maintenance olaparib and bevacizumab in ovarian cancer patients aged ≥65 years from the PAOLA-1/ENGOT-ov25 trial.
  9. Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA.
  10. Molecular characteristics and clinical behaviour of epithelial ovarian cancers.
  11. Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.
  1. Sci Rep. 2023 Jan 06. 13(1): 278
    Identification of TP53 mutations in circulating tumour DNA in high grade serous ovarian carcinoma using next generation sequencing technologies.
    Leslie Calapre, Tindaro Giardina, Aaron B Beasley, Anna L Reid, Colin Stewart, Benhur Amanuel, Tarek M Meniawy, Elin S Gray.
      Plasma circulating tumour DNA (ctDNA) has been suggested to be a viable biomarker of response to treatment in patients with high grade serous ovarian carcinoma (HGSOC). TP53 mutations are present in more than 90% of HGSOCs but somatic variants are distributed across all exonic regions of the gene, requiring next generation sequencing (NGS) technologies for mutational analysis. In this study, we compared the suitability of the Accel (Swift) and Oncomine (ThermoFisher) panels for identification of TP53 mutations in ctDNA of HGSOC patients (N = 10). Only 6 patients (60%) were found to have TP53 mutations using the ACCEL panel but the addition of molecular tags in the Oncomine panel improved ctDNA detection with at least one mutation detected in all cases (100%). Orthogonal validation of the 14 somatic variants found by Oncomine, using droplet digital PCR, confirmed 79% (11/14) of the identified mutations. Overall, the Oncomine panel with unique molecular identifiers (UMI) appears more useful for ctDNA analysis in HGSOC.
    DOI:  https://doi.org/10.1038/s41598-023-27445-2
  2. Int J Gynecol Cancer. 2023 Jan 11. pii: ijgc-2022-003993. [Epub ahead of print]
    Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse.
    Flora Brouillard-Saby, Caroline Saint-Martin, Isabelle Ray-Coquard, Laurence Gladieff, Christophe Pomel, Pierre-Emmanuel Colombo, Jean-Marc Classe, Marion Chevrier, Florence Joly, Thibault De la Motte Rouge, Anne Floquet, Renaud Sabatier, Emmanuel Barranger, Hélène Costaz, Eric Leblanc, Frédéric Marchal, Patricia Pautier, Lise Bosquet, Manuel Rodrigues.
       OBJECTIVE: Chemotherapy for high-grade serous ovarian cancers in platinum-sensitive relapse includes carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin. According to in vitro data, BRCA mutated patients are sensitive to replicative stress agents but BRCA status is not yet used for the choice of chemotherapy at relapse. Our aim was to assess these doublets according to BRCA status in first platinum-sensitive relapse.
    METHODS: The ESME ovarian cancer database comprises a multicenter retrospective cohort of patients with ovarian cancer treated in French cancer centers between January 2011 and December 2017. Patients with high-grade serous ovarian cancers at first platinum-sensitive relapse who received one of these doublets were included. The objective was to compare progression-free survival of each chemotherapy doublet according to BRCA status.
    RESULTS: Among the 10 263 patients in the database, 1539 patients had a first platinum-sensitive relapse: 825 BRCA wild type patients (53.6%) and 304 BRCA mutated patients (19.8%) (7 patients had a homologous recombination mutation and BRCA status was unkown for 403 patients). Median progression-free survival was longer in BRCA mutated patients than in BRCA wild type patients when receiving carboplatin/pegylated liposomal doxorubicin without maintenance treatment (15.8 vs 11.8 months; p<0.001). In contrast, we observed no difference in patients treated with carboplatin/paclitaxel (14.6 vs 14.3 months, respectively; p=0.70) or in those treated with carboplatin/gemcitabine (12.0 vs 9.8 months, respectively; p=0.18). In BRCA wild type patients without maintenance, better progression-free survival occurred with carboplatin/paclitaxel (median progression-free survival 14.3 months) than with carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin (9.8 and 11.8 months, respectively; p=0.017). In BRCA mutated patients without maintenance, there was no difference between the three doublets (median progression-free survival of 14.6, 12.0, and 15.8 months with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin, respectively; p=0.40).
    CONCLUSION: While treatment with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin shows comparable efficacy in BRCA mutated patients, treatment with carboplatin/paclitaxel appears to be more effective than carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin in BRCA wild type patients with high-grade serous ovarian cancers at first platinum-sensitive relapse.
    Keywords:  BRCA1 Protein; Cystadenocarcinoma, Serous; Gynecology; Neoplasm Recurrence, Local; Ovarian Cancer
    DOI:  https://doi.org/10.1136/ijgc-2022-003993
  3. J Clin Med. 2022 Dec 30. pii: 296. [Epub ahead of print]12(1):
    Prophylactic Salpingectomy during Hysterectomy for Benign Disease: A Prospective Study to Evaluate High-Grade Serous Ovarian Carcinoma Precursors.
    Garri Tchartchian, Bernd Bojahr, Lucas Heils, Harald Krentel, Rudy L De Wilde.
      Recent findings suggest that high-grade serous ovarian cancer can originate in the fallopian tube. Not only has that made the identification of precursor lesions pivotal in early detection and prevention of these cancers, prophylactic salpingectomy alongside hysterectomy for benign indications has been increasingly proposed as well. The present prospective single-center study included 273 women who underwent opportunistic salpingectomy alongside laparoscopic supracervical hysterectomy. Uterine and tubal histopathological results as well as intra- and postoperative complications were evaluated. The complication rate was 3.3%, of which none were caused by salpingectomy. Uterine histopathology diagnosed 181 patients (66.8%) with uterine myomas, 60 patients (22.1%) with adenomyosis, 29 patients (10.7%) with adenomyomatosis, and, 1 patient (0.4%) without pathological abnormality. p53 signatures were detected in 221 right fallopian tubes (80.9%) and in 229 left tubes (83.9%). In total, 8 patients showed bilateral STIL (2.9%), whereas in 1 patient (0.4%) STIL was detected in the left tube only. No STIC were detected. Laparoscopic opportunistic salpingectomy is demonstrated to be both safe and feasible. It appears to be promising to reduce the risk for ovarian cancer, yet more studies are needed to undoubtedly confirm this.
    Keywords:  LASH; STIL; hysterectomy; laparoscopic; opportunistic salpingectomy; p53
    DOI:  https://doi.org/10.3390/jcm12010296
  4. Sci Rep. 2023 Jan 13. 13(1): 730
    Diagnostic and prognostic potential of the microbiome in ovarian cancer treatment response.
    Abigail E Asangba, Jun Chen, Krista M Goergen, Melissa C Larson, Ann L Oberg, Jvan Casarin, Francesco Multinu, Scott H Kaufmann, Andrea Mariani, Nicholas Chia, Marina R S Walther-Antonio.
      Ovarian cancer (OC) is the second most common gynecological malignancy and the fifth leading cause of death due to cancer in women in the United States mainly due to the late-stage diagnosis of this cancer. It is, therefore, critical to identify potential indicators to aid in early detection and diagnosis of this disease. We investigated the microbiome associated with OC and its potential role in detection, progression as well as prognosis of the disease. We identified a distinct OC microbiome with general enrichment of several microbial taxa, including Dialister, Corynebacterium, Prevotella, and Peptoniphilus in the OC cohort in all body sites excluding stool and omentum which were not sampled from the benign cohort. These taxa were, however, depleted in the advanced-stage and high-grade OC patients compared to early-stage and low-grade OC patients suggestive of decrease accumulation in advanced disease and could serve as potential indicators for early detection of OC. Similarly, we also observed the accumulation of these mainly pathogenic taxa in OC patients with adverse treatment outcomes compared to those without events and could also serve as potential indicators for predicting patients' responses to treatment. These findings provide important insights into the potential use of the microbiome as indicators in (1) early detection of and screening for OC and (2) predicting patients' response to treatment. Given the limited number of patients enrolled in the study, these results would need to be further investigated and confirmed in a larger study.
    DOI:  https://doi.org/10.1038/s41598-023-27555-x
  5. Sci Transl Med. 2023 Jan 11. 15(678): eabm6863
    Genome-wide analysis of aberrant position and sequence of plasma DNA fragment ends in patients with cancer.
    Karan K Budhraja, Bradon R McDonald, Michelle D Stephens, Tania Contente-Cuomo, Havell Markus, Maria Farooq, Patricia F Favaro, Sydney Connor, Sara A Byron, Jan B Egan, Brenda Ernst, Timothy K McDaniel, Aleksandar Sekulic, Nhan L Tran, Michael D Prados, Mitesh J Borad, Michael E Berens, Barbara A Pockaj, Patricia M LoRusso, Alan Bryce, Jeffrey M Trent, Muhammed Murtaza.
      Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC content [information-weighted fraction of aberrant fragments (iwFAF)]. We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and nine nucleotide frequencies from three positions surrounding fragment ends, we developed a machine learning model to differentiate healthy individuals from patients with cancer. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.
    DOI:  https://doi.org/10.1126/scitranslmed.abm6863
  6. Nat Methods. 2023 Jan 07.
    Parts-based decomposition of spatial genomics data finds distinct tissue regions.
      
    DOI:  https://doi.org/10.1038/s41592-022-01725-7
  7. Nat Genet. 2023 Jan;55(1): 1
    Genetics of clonal hematopoiesis.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-022-01290-x
  8. Eur J Cancer. 2022 Dec 10. pii: S0959-8049(22)01779-8. [Epub ahead of print]181 42-52
    Efficacy and safety of maintenance olaparib and bevacizumab in ovarian cancer patients aged ≥65 years from the PAOLA-1/ENGOT-ov25 trial.
    Renaud Sabatier, Frédérique Rousseau, Florence Joly, Claire Cropet, Coline Montégut, Johanna Frindte, Saverio Cinieri, Eva M Guerra Alía, Stephan Polterauer, Hiroyuki Yoshida, Ignace Vergote, Nicoletta Colombo, Sakari Hietanen, Rémi Largillier, Ulrich Canzler, Alain Gratet, Frederik Marmé, Laure Favier, Eric Pujade-Lauraine, Isabelle Ray-Coquard.
       BACKGROUND: The phase III PAOLA-1/ENGOT-ov25 study (NCT02477644) showed that addition of olaparib to bevacizumab maintenance improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer. We evaluated maintenance olaparib plus bevacizumab in older patients in PAOLA-1.
    METHODS: Baseline clinical and molecular data, and PFS, were compared between older (aged ≥65 years) and younger patients (<65 years). Factors associated with olaparib efficacy, and safety in age subgroups, were also assessed.
    RESULTS: Of 806 randomised patients, 292 (36.2%) were ≥65 years. A lower proportion of older versus younger patients had an Eastern Cooperative Oncology Group performance status of 0 (61.0% versus 76.2%) and upfront surgery (42.0% versus 55.7%). Older patients were less likely to have a BRCA1/2 mutation (17.1% versus 36.7%) or homologous recombination deficiency-positive status (34.1% versus 55.7%). After median follow-up of 22.1 months, median PFS was 21.6 months with olaparib versus 16.6 months with placebo in the older population (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.41-0.75), comparable with the younger population (median 22.9 versus 16.9 months; HR 0.61, 95% CI 0.49-0.77). PFS benefits were observed in patients with a BRCA mutation or homologous recombination deficiency-positive tumours. Incidence of olaparib-related grade ≥3 adverse events in older patients was comparable with that of younger patients (36.8% versus 31.7%) although hypertension and anaemia were more common in older patients. No treatment-related deaths occurred in older patients receiving olaparib.
    CONCLUSION: Older patients enrolled in PAOLA-1 achieved similar PFS benefits compared with younger patients, with a similar safety profile.
    Keywords:  Elderly; Olaparib; Ovarian cancer; Safety; Survival
    DOI:  https://doi.org/10.1016/j.ejca.2022.11.029
  9. Brief Bioinform. 2023 Jan 05. pii: bbac575. [Epub ahead of print]
    Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA.
    Eva María Trinidad, Enrique Vidal, Esther Coronado, Anna Esteve-Codina, Victoria Castel, Adela Cañete, Marta Gut, Simon Heath, Jaime Font de Mora.
      Analysis of the methylome of tumor cell-free deoxyribonucleic acid (DNA; cfDNA) has emerged as a powerful non-invasive technique for cancer subtyping and prognosis. However, its application is frequently hampered by the quality and total cfDNA yield. Here, we demonstrate the feasibility of very low-input cfDNA for whole-methylome and copy-number profiling studies using enzymatic conversion of unmethylated cysteines [enzymatic methyl-seq (EM-seq)] to better preserve DNA integrity. We created a model for predicting genomic subtyping and prognosis with high accuracy. We validated our tool by comparing whole-genome CpG sequencing with in situ cohorts generated with bisulfite conversion and array hybridization, demonstrating that, despite the different techniques and sample origins, information on cfDNA methylation is comparable with in situ cohorts. Our findings support use of liquid biopsy followed by EM-seq to assess methylome of cancer patients, enabling validation in external cohorts. This advance is particularly relevant for rare cancers like neuroblastomas where liquid-biopsy volume is restricted by ethical regulations in pediatric patients.
    Keywords:  11q; DNA methylation; MYCN; combined haploinsufficiency; high-risk; liquid biopsy; neuroblastoma
    DOI:  https://doi.org/10.1093/bib/bbac575
  10. Cancer Lett. 2023 Jan 07. pii: S0304-3835(23)00008-3. [Epub ahead of print]555 216057
    Molecular characteristics and clinical behaviour of epithelial ovarian cancers.
    Robert L Hollis.
      Ovarian carcinoma (OC) is an umbrella term for multiple distinct diseases (histotypes), each with their own developmental origins, clinical behaviour and molecular profile. Accordingly, OC management is progressing away from a one-size-fits all approach, toward more molecularly-driven, histotype-specific management strategies. Our knowledge of driver events in high grade serous OC, the most common histotype, has led to major advances in treatments, including PARP inhibitor use. However, these agents are not suitable for all patients, most notably for many of those with rare OC histotypes. Identification of additional targeted therapeutic strategies will require a detailed understanding of the molecular landscape in each OC histotype. Until recently, tumour profiling studies in rare histotypes were sparse; however, significant advances have been made over the last decade. In particular, reports of genomic characterisation in endometrioid, clear cell, mucinous and low grade serous OC have significantly expanded our understanding of mutational events in these tumour types. Nonetheless, substantial knowledge gaps remain. This review summarises our current understanding of each histotype, highlighting recent advances in these unique diseases and outlining immediate research priorities for accelerating progress toward improving patient outcomes.
    Keywords:  Clear cell ovarian cancer; Endometrioid ovarian cancer; High grade serous ovarian cancer; Low grade serous ovarian cancer; Molecular profiling; Mucinous ovarian cancer; Ovarian cancer; Ovarian carcinoma; Ovarian carcinosarcoma; Survival; Treatment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216057
  11. Life Sci. 2023 Jan 04. pii: S0024-3205(22)01061-X. [Epub ahead of print]315 121361
    Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.
    Elmira Roshani Asl, Davoud Rostamzadeh, Pascal H G Duijf, Sahar Mafi, Behnaz Mansoori, Shirin Barati, William C Cho, Behzad Mansoori.
      TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.
    Keywords:  Cancer; Cancer-associated fibroblasts; Extracellular matrix; Mutated p53; TP53; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.lfs.2022.121361
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:26.