bims-ovdlit 2026-06-28 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2026–06–28
eight papers selected by
Lara Paracchini, Humanitas Research

Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity.
International Trends in Concurrent Hysterectomy at Risk-Reducing Surgery in BRCA1/2 pathogenic variant carriers: A mixed-methods study.
The Clinical Application of Refined Risk Estimates (caRe) Study in BRCA1 and BRCA2 Pathogenic Variant Carriers: A Randomized Controlled Trial.
Spectrum of double heterozygosity in individuals diagnosed with hereditary breast and ovarian cancer.
Three decades of cancer genetics.
Evaluating the utility of circulating cell-free DNA in the context of endometrial cancer: a systematic scoping review.
Perioperative ctDNA as a prognostic biomarker in endometrial cancer - the CODEC study.
AI in variant analysis: fast track to genetic diagnoses.

Am J Hum Genet. 2026 Jun 23. pii: S0002-9297(26)00225-9. [Epub ahead of print]

Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity.

Simon Schnaiter, Frédéric R Santer, Katalin A Csanaky, Louise Adel Jensen, Alain G Zeimet, Kyriaki Michailidou, Amanda B Spurdle, Mads Thomassen.

  Homologous recombination deficiency (HRD) drives oncogenesis and therapeutic vulnerability in high-grade ovarian cancer (HGOC). While HRD testing is widely used to guide platinum- and especially poly(ADP-ribose) polymerase (PARP)-inhibitor-based therapies, its potential to provide evidence for BRCA1 and BRCA2 variant classification under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) framework has not been assessed. In this Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium project, a literature review identified four independent HGOC cohorts reporting details on both BRCA1 and BRCA2 pathogenic variant (BRCApv) status and HRD-related genomic instability scores (HRD-GISs), all determined by the Myriad MyChoice HRD+ CDx assay. Likelihood ratios (LRs) were calculated to assess the probability that a BRCA1 or BRCA2 variant is pathogenic with a given HRD-GIShigh (≥42) or HRD-GISlow (<42) tumor status, and these LRs were mapped to ACMG/AMP evidence strength categories defined by Bayesian modeling. Across the pooled dataset of 4,943 tumors (765 BRCApv and 4,178 BRCA1 or BRCA2 wild type [BRCAwt]), 91.0% of BRCApv and 30.0% of BRCAwt tumors were HRD-GIShigh. The LR for a BRCA1 or BRCA2 variant being pathogenic in an HRD-GIShigh HGOC was 3.03 (95% confidence interval [CI]: 2.88-3.19), corresponding to supporting pathogenic evidence. Conversely, the pooled LR for a variant being pathogenic in an HRD-GISlow HGOC was 0.13 (95% CI: 0.10-0.16), corresponding to moderate benign evidence. The HGOC HRD-GIS determined by the MyChoice HRD+ CDx assay provides statistically robust evidence for BRCA1 and BRCA2 variant interpretation. This approach may refine variant classification, particularly for variants of uncertain significance, and enhance clinical decision-making in hereditary and tumor-based cancer risk assessment.

Keywords:  BRCA; HRD; VUS; cancer risk; genomic instability; ovarian cancer; variant classification

DOI:  https://doi.org/10.1016/j.ajhg.2026.05.015
Am J Obstet Gynecol. 2026 Jun 20. pii: S0002-9378(26)00324-8. [Epub ahead of print]

International Trends in Concurrent Hysterectomy at Risk-Reducing Surgery in BRCA1/2 pathogenic variant carriers: A mixed-methods study.

TUBA WISP Hysterectomy Consortium

   BACKGROUND: BRCA1/2 pathogenic variant (PV) carriers are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO) between the ages of 35 to 45 due to their increased risk of tubo-ovarian cancer. A concurrent hysterectomy may be performed at the time of RRSO. Currently, the international execution of hysterectomy during risk-reducing surgery and the factors guiding related decision-making are unknown.
METHODS: We conducted a mixed-methods study. First, we executed a quantitative analysis with data from the WISP and TUBA-WISP II study, both prospective preferential trials assessing surgical strategies for tubo-ovarian cancer prevention. Data was collected via electronic case report forms. Concurrent hysterectomy during RRSO was compared between Europe, North- and South America, and Australia using Kruskal-Wallis tests. We used univariable logistic regression models to estimate the association of personal and prevention-related characteristics with the execution of hysterectomy at RRSO in women from North- and South America. Subsequently, we conducted focus group interviews with gynecologic providers from 12 countries who provide preventive care for individuals at increased risk of tubo-ovarian cancer to identify indications, barriers, and facilitators for the execution of hysterectomy with RRSO.
RESULTS: In the quantitative analysis we included 2181 participants, of which 1647 (75.5%) were from Europe, 498 (22.8%) from North-and South America, and 36 (1.7%) from Australia. Execution of hysterectomy at RRSO differed substantially between continents, with an execution of 48.8% in North- and South America, 14.2% in Australia, and 2.8% in Europe (p<0.001). Execution of concurrent hysterectomy at RRS in women from North- and South America occurred more often in women with a BRCA1 PV compared to a BRCA2 PV (adjusted odds ratio 0.4 (95% confidence interval 0.2-0.7). In the qualitative analysis, we interviewed 23 healthcare providers and identified 31 barriers and 32 facilitators regarding hysterectomy execution during RRSO. A total of eight different indications were mentioned, but opinions varied on the validity and weight given to each indication. Providers indicated that important barriers or facilitators for concurrent hysterectomy included a lack of clear guidelines, cultural variation between countries, (lack of) consensus within departments, and different interpretation of the endometrial cancer risk.
CONCLUSIONS: Internationally, there is a large variation in execution of hysterectomy during risk-reducing surgery with frequent utilization in North and South America, and rare utilization in Europe. This could be explained by the interpretation of indications for hysterectomy by providers, which might be explained by cultural variation, the absence of clear guidelines, and limited scientific evidence.

Keywords:  brca1; brca2; endometrial cancer; hysterectomy; ovarian cancer; prevention

DOI:  https://doi.org/10.1016/j.ajog.2026.06.017
Cancer Prev Res (Phila). 2026 Jun 24.

The Clinical Application of Refined Risk Estimates (caRe) Study in BRCA1 and BRCA2 Pathogenic Variant Carriers: A Randomized Controlled Trial.

Leigha Senter, Shelly Hovick, Rachel Notestine, Lauren Norden, Nadia Benny, Shannon Phillips, Ava Willoughby, Robert Pyatt, Doreen Agnese, Julie S Mak, Allison DePersia, Sarah V Colonna, Whitney F Maxwell, Wendy Kohlmann, Erika L Spaeth, Ora Gordon, Darcy Thull, Guy N Brock, Amy Webb, Rachel M Smith, Amanda Ewart Toland.

Individuals with germline BRCA1 or BRCA2 pathogenic variants (PVs) may struggle with risk management decision-making. Advancements in technology could provide more specific risk information to patients, but the impact of this information is unknown. The Clinical Application of Refined Risk Estimates Study is a two-arm randomized controlled trial in women with a BRCA1/BRCA2 PV. The primary objective was to determine whether genotype-informed cancer risk estimates (GRE) compared to standard lifetime cancer risk estimates (SRE) decreased decisional conflict related to cancer risk management decision-making. Women were recruited following disclosure of their PV results. Participants completed a baseline survey and were randomized 1:1 to receive a GRE or SRE. After receiving their results, participants completed a follow-up survey. Likert and continuous data measures were analyzed using linear regression. There were no differences in decisional conflict between study arms at follow-up. However, individuals in the SRE arm showed an increased need for personal structure compared to those in the GRE arm (p =0.02). Compared to baseline, individuals within the SRE arm showed decreased decisional conflict (p =0.003) and increased perceived stress (p =0.02) at follow-up. A more personalized cancer risk estimate did not decrease decisional conflict in women with BRCA1/BRCA2 PVs. Future studies will determine whether a GRE impacts actual decision-making behaviors.

DOI: https://doi.org/10.1158/1940-6207.CAPR-26-0044
Eur J Cancer. 2026 Jun 11. pii: S0959-8049(26)00655-6. [Epub ahead of print]244 116874

Spectrum of double heterozygosity in individuals diagnosed with hereditary breast and ovarian cancer.

Natalie Herold, Christoph Engel, Dorothee Speiser, Tim Ripperger, Andrea Gehrig, Nadia Harbeck, Norbert Arnold, Nicola Dikow, Susanne Ledig, Elena Leinert, Matthias Rath, Jan Hauke, Susanne Morlot, Nina Ditsch, Julia Ritter, Britta Blümcke, Jörg Schröder, Anke Waha, Anna Hester, Monika Maringa, Bernadette A S Jäger, Rita Schmutzler, Pauline Wimberger, Barbara Wappenschmidt, Bjoern Sander, Christine Solbach, Bernhard H F Weber, Tobias Blaum, Christopher Schroeder, Alexander E Volk, Bahriye Aktas, Marion Kiechle, Cornelia Meisel, Tanja Fehm, Eric Hahnen, Bernd Auber, Kerstin Rhiem, Monika M Golas.

   BACKGROUND: (Likely) pathogenic variants (pVs) in hereditary breast and/or ovarian cancer (HBOC) genes increase cancer risk, but the clinical implications of multiple pVs remain insufficiently understood.
METHODS: Using data from the prospective nationwide German Consortium for HBOC registry, we conducted a case-control study of genotype-phenotype associations, matching female carriers to compare cancer risk and disease severity between multiple and single heterozygous (SH) pV carriers.
RESULTS: Among 26,983 carriers of single or multiple HBOC-associated pVs, 409 individuals had multiple heterozygosities, including 400 double heterozygous (DH) carriers. In a subcohort tested for 13 core genes, 98/3407 (2.9%) individuals had multiple HBOC-associated pVs. Breast cancers (BCs) in DH women with pVs in BRCA1 and another gene were predominantly triple-negative, even when the second, non-BRCA1 pV was typically associated with hormone receptor (HR)-positive BC. By contrast, BRCA1/CHEK2 DH carriers showed more HR-positive BCs than BRCA1 SH women. The median age at first BC was similar in female ATM/CHEK2 DH carriers and BRCA1 SH carriers (41.5 [IQR 14.0] vs. 41.3 [14.1] years). Matched BRCA1 and BRCA2 SH carriers were less likely to present with higher disease severity than BRCA1/BRCA2 DH carriers (BRCA1: OR 0.396 [0.180-0.87]; BRCA2: OR 0.224 [0.100-0.50]).
CONCLUSIONS: Multiple heterozygosity in HBOC core genes is more frequent than previously assumed. Our data indicate that gene-gene constellations can reshape tumour phenotype and clinical severity rather than following single-gene expectations. Integrating multiple pVs into risk assessment and counselling may enhance personalised surveillance and risk-reducing strategies for DH individuals and their families in the era of widespread multigene testing.

Keywords:  Germline; Hereditary breast and ovarian cancer; MINAS; Multiple heterozygosity; Phenotype-genotype; Severity score

DOI:  https://doi.org/10.1016/j.ejca.2026.116874
Nat Genet. 2026 Jun 26.

Three decades of cancer genetics.

Petra Gross.

DOI: https://doi.org/10.1038/s41588-026-02657-0
Int J Gynecol Cancer. 2026 May 19. pii: S1048-891X(26)00298-7. [Epub ahead of print]36(8): 104767

Evaluating the utility of circulating cell-free DNA in the context of endometrial cancer: a systematic scoping review.

Eliza R Macdonald, Grace Rose, David Simar, Alexandra L McCarthy, Caroline Ford, Kristina Warton, Sandra Hayes, Briana K Clifford.

   OBJECTIVE: Elevated concentrations of circulating cell-free DNA and circulating tumor DNA (ctDNA) are often detectable in biofluid from individuals with cancer. Investigating cfDNA and ctDNA across the endometrial cancer continuum provides insight into diagnostic and prognostic potential. This systematic scoping review provides an overview of studies evaluating the utility of cell-free DNA ± circulating tumor DNA in endometrial cancer.
METHODS: Databases and clinical trials registries (Embase, PubMed, CINAHL, Scopus, Open Science Framework, ClinicalTrials.gov) were searched using terms related to "Endometrial cancer", "Cell-free DNA", and "Circulating tumour DNA". Primary articles and pre-registered protocols of observational or interventional studies reporting cell-free DNA ±ctDNA measurement using biofluid from individuals with endometrial cancer of any stage, grade, or sub-type, at any time point were included.
RESULTS: Ninety-three records were identified. Studies evaluated cell-free DNA ± circulating tumor DNA in endometrial cancer for 1) diagnosis; 2) monitoring disease status; 3) molecular profiling; 4) determining prognostic risk. Cell-free DNA ± circulating tumor DNA was primarily isolated from blood and analyzed using PCR-based assays or Next Generation Sequencing. Circulating tumor DNA showed promising diagnostic performance with greater potential in endometrial cancer prognosis, profiling, and monitoring, compared to cell-free DNA. Study design, sample characteristics, and data collection, analysis, and reporting were heterogeneous, limiting the strength of evidence for any given relationship.
CONCLUSIONS: Cell-free DNA ± circulating tumor DNA has promising potential as a clinically valuable marker in endometrial cancer diagnosis, tumor profiling, treatment, and surveillance. However, evidence supporting the clinical use of any given cell-free DNA ± circulating tumor DNA parameter in this cohort is immature and limited by the lack of standardized methods and reporting. Addressing study design limitations, standardizing analysis methods and outcome reporting, and improving understanding of cell-free DNA physiology represent opportunities to advance this field of clinical research.

Keywords:  Biomarker; Cell-Free DNA; Circulating Tumor DNA; Endometrial Cancer; Liquid Biopsy; Uterine Cancer

DOI:  https://doi.org/10.1016/j.ijgc.2026.104767
Transl Oncol. 2026 Jun 22. pii: S1936-5233(26)00208-1. [Epub ahead of print]71 102871

Perioperative ctDNA as a prognostic biomarker in endometrial cancer - the CODEC study.

Rachel L Delahunty, Madawa Jayawardana, Rainier Arnolda, Thuan Tzen Koh, Michael S Hofman, Kym Reid, Julie Lamont, Caitlyn Nguyen-Ngo, Hayley M Johnston, Nicole G Brooks, Patricia Wojtowicz, Vanessa J Obers, Thomas Jobling, Clair Shadbolt, Paul E Smith, Brooke L Sawyer, Huiling Xu, S Sandun M Silva, Deborah Neesham, Jennifer Ellis, Geraldine Goss, Mila Volchek, Kate Jones, Chelsee A Hewitt, Andrew Fellowes, Henry M Prince, Orla McNally, Stephen Q Wong, Elizabeth L Christie, Costas K Yannakou.

   PURPOSE: Biomarkers to predict relapse and guide adjuvant therapy selection are needed in endometrial cancer (EC), one of the few cancers increasing in incidence and mortality. Assessment of circulating tumour DNA (ctDNA) at multiple perioperative time points has not been explored in EC. This study aimed to evaluate the prognostic utility of ctDNA across four perioperative time points, explore ctDNA dynamics, and compare ctDNA-derived tumour burden with 18F-fluorodeoxyglucose (FDG)-PET/CT and MRI.
PATIENTS AND METHODS: Participants with Type 2 EC planned for surgery and consenting to the collection of biospecimens were enrolled prior to surgery and followed prospectively. Participants had preoperative imaging, and tumour sequencing was performed using hybrid capture, which guided the design of droplet digital PCR (ddPCR) assays for ctDNA analysis. The primary study endpoint was relapse free survival.
RESULTS: Fifty participants were enrolled in the CODEC study. Genomic findings were consistent with the established molecular landscape of EC. Detection of ctDNA postoperatively at 24 h (Time Point 2B) and at 2-6 weeks (Time Point 3) was associated with poorer relapse-free survival. No significant association with outcome was observed for preoperative (Time Point 1) or intraoperative (Time Point 2A) ctDNA. Preoperative ctDNA correlated with FDG-PET- and MRI-defined tumour volume.
CONCLUSION: These findings are hypothesis-generating and support the prognostic relevance of postoperative ctDNA assessment in EC with the 2-6 week postoperative window the most clinically informative time point for detecting minimal residual disease. Further studies are required to validate these findings and determine whether ctDNA can guide adjuvant therapy selection.

Keywords:  Biomarkers; Endometrial cancer; Risk stratification; ctDNA

DOI:  https://doi.org/10.1016/j.tranon.2026.102871
Hum Genet. 2026 Jun 26. pii: 54. [Epub ahead of print]145(1):

AI in variant analysis: fast track to genetic diagnoses.

Elizabeth J Wilk, Sasha Taluri, Timothy C Howton, Anthony B Crumley, Michal Mrug, Brittany N Lasseigne.

While falling costs have expanded access to genomic sequencing, clinical utility is frequently hindered by the challenge of interpreting complex genetic data. Variant analysis for rare disease patients especially requires significant time and expertise, creating a bottleneck that delays diagnostics. Although advances in genetic variant classification have improved diagnostic precision, they have also increased the identification of variants of uncertain significance (VUSs), widening the interpretation gap between data generation and clinical actionability. The high prevalence of VUSs can lead to false reassurance or psychological distress by misinterpretting inconclusive results. We propose that artificial intelligence (AI) is a critical clinical decision-support tool for bridging this gap, offering a scalable framework to optimize variant interpretation and shorten the diagnostic odyssey. While reclassification ultimately requires biological evidence that AI cannot replace, these tools serve as essential aggregators and prioritizers, especially as guidelines transition toward the upcoming quantitative ACMG v4 framework. We advocate integrating AI throughout the genetic diagnostic workflow-from initial phenotyping to variant prioritization-to facilitate data-driven, personalized treatment. We outline current AI-assisted approaches and discuss anticipated challenges in this pursuit, such as privacy, training data bias and quality, model explainability, and the necessity of a total product life cycle for validation. To address these challenges, we provide recommendations for "human-in-the-loop" design and intuitive workflow integration to ensure AI tools meet the highest standards of precision, reproducibility, and transparency to maximize adoption. By standardizing AI across the variant analysis pipeline, we can fast-track the path to genetic diagnoses, effectively bridging the interpretation gap and enabling rapid delivery of personalized medical interventions.

DOI: https://doi.org/10.1007/s00439-026-02847-0