bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2023‒11‒26
seven papers selected by
Lara Paracchini, Humanitas Research

  1. medRxiv. 2023 Nov 10. pii: 2023.11.09.23298321. [Epub ahead of print]
    Flurina A M Saner, Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A Zwimpfer, Nicola S Meagher, Sian Fereday, Laura Twomey, Kathleen I Pishas, Therese Hoang, Adelyn Bolithon, Nadia Traficante, Kathryn Alsop, Elizabeth L Christie, Eun-Young Kang, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Jennifer Alsop, Matthias W Beckmann, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Paul R Harnett, Holly R Harris, Arndt Hartmann, Alexander Hein, Joy Hendley, Aocs Group, Brenda Y Hernandez, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Björg Kristjansdottir, Nhu D Le, Marcin Lener, Jenny Lester, Jan Lubiński, Constantina Mateoiu, Sandra Orsulic, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, Naveena Singh, T Rinda Soong, Helen Steed, Paniti Sukumvanich, Aline Talhouk, Sarah E Taylor, Robert A Vierkant, Chen Wang, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Michael S Anglesio, Andrew Berchuck, James D Brenton, Ian Campbell, Linda S Cook, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, Marc T Goodman, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Usha Menon, Francesmary Modugno, Paul D P Pharoah, Joellen M Schildkraut, Karin Sundfeldt, Anthony J Swerdlow, Ellen L Goode, Anna DeFazio, Martin Köbel, Susan J Ramus, David D L Bowtell, Dale W Garsed.
      Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 ( BRCA ). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss.
    Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 × 10 -7 ), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC ( P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 x10 -6 ) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin ( P < 0.01) and paclitaxel ( P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA -deficient HGSC with co-loss of RB1 .
    Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
  2. Gynecol Oncol. 2023 Nov 17. pii: S0090-8258(23)01532-9. [Epub ahead of print]179 123-130
      OBJECTIVE: UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers.METHODS: In UKCTOCS, 202638 postmenopausal women, aged 50-74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978;
    RESULTS: 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms.
    CONCLUSIONS: Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.
    Keywords:  GOFF index; NICE; Ovarian cancer; Symptoms; UKCTOCS
  3. BMJ Case Rep. 2023 Nov 23. pii: e255638. [Epub ahead of print]16(11):
      Primary fallopian tube carcinoma (PFTC) is a rare disease. Its location, close association with epithelial ovarian carcinoma, and lack of specific signs and symptoms make diagnosis challenging especially in its early stages. We report a postmenopausal patient who presented with a 2-month history of abdominopelvic pain with watery vaginal discharge. Imaging findings showed a 7 cm complex left adnexal mass. The patient underwent a robotic-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy and surgical staging. Findings were significant for stage IA serous fallopian tube carcinoma. PFTC is sometimes missed preoperatively and intraoperatively. Available literature review has focused on the clinical and imaging characteristics of PFTC to aid in timely disease diagnosis. Minimally invasive surgery is a viable option in the diagnosis and management of early-stage ovarian cancer due to improved visualisation of pelvic structures, decreased length of hospital stay, decreased estimated blood loss and lower postoperative complication rates compared with laparotomy.
    Keywords:  Cancer - see Oncology; Gynecological cancer; Surgical oncology
  4. Nat Biotechnol. 2023 Nov 20.
      Mucosal and barrier tissues, such as the gut, lung or skin, are composed of a complex network of cells and microbes forming a tight niche that prevents pathogen colonization and supports host-microbiome symbiosis. Characterizing these networks at high molecular and cellular resolution is crucial for understanding homeostasis and disease. Here we present spatial host-microbiome sequencing (SHM-seq), an all-sequencing-based approach that captures tissue histology, polyadenylated RNAs and bacterial 16S sequences directly from a tissue by modifying spatially barcoded glass surfaces to enable simultaneous capture of host transcripts and hypervariable regions of the 16S bacterial ribosomal RNA. We applied our approach to the mouse gut as a model system, used a deep learning approach for data mapping and detected spatial niches defined by cellular composition and microbial geography. We show that subpopulations of gut cells express specific gene programs in different microenvironments characteristic of regional commensal bacteria and impact host-bacteria interactions. SHM-seq should enhance the study of native host-microbe interactions in health and disease.
  5. Life (Basel). 2023 Nov 10. pii: 2192. [Epub ahead of print]13(11):
      Somatic copy number alterations (SCNAs) are frequently observed in high-grade ovarian serous carcinoma (HGOSC). However, their impact on gene expression levels has not been systematically assessed. In this study, we explored the relationship between recurrent SCNA and gene expression using The Cancer Genome Atlas Pan Cancer dataset (OSC, TCGA, PanCancer Atlas) to identify cancer-related genes in HGOSC. We then investigated any association between highly correlated cancer genes and clinicopathological parameters, including age of diagnosis, disease stage, overall survival (OS), and progression-free survival (PFS). A total of 772 genes with recurrent SCNAs were observed. SCNA and mRNA expression levels were highly correlated for 274 genes; 24 genes were classified as a Tier 1 gene in the Cancer Gene Census in the Catalogue of Somatic Mutations in Cancer (CGC-COSMIC). Of these, 11 Tier 1 genes had highly correlated SCNA and mRNA expression levels: TBL1XR1, PIK3CA, UBR5, EIF3E, RAD21, EXT1, RECQL4, KRAS, PRKACA, BRD4, and TPM4. There was no association between gene amplification and disease stage or PFS. EIF3E, RAD21, and EXT1 were more frequently amplified in younger patients, specifically those under the age of 55 years. Patients with tumors carrying PRKACA, BRD4, or TPM4 amplification were associated with a significantly shorter OS. RECQL4 amplification was more frequent in younger patients, and tumors with this amplification were associated with a significantly better OS.
    Keywords:  gene expression; high-grade ovarian serous carcinoma; somatic copy number aberration
  6. Maturitas. 2023 Nov 11. pii: S0378-5122(23)00492-9. [Epub ahead of print] 107886
    Keywords:  BRCA mutation carriers; Hereditary cancer; Menopausal hormone therapy; Menopause; Oophorectomy