bims-ovdlit 2026-05-24 papers

Issue of 2026–05–24
eight papers selected by
Lara Paracchini, Humanitas Research

Crit Rev Oncol Hematol. 2026 May 18. pii: S1040-8428(26)00270-2. [Epub ahead of print] 105383

First-Line Immunotherapy With or Without PARP Inhibitors in Advanced Ovarian Cancer: A Meta-Analysis including Bevacizumab Use, Molecular Status, and PD-L1 Expression.

Claudia Marchetti, Carolina Maria Sassu, Amedeo Cefaliello, Giorgia Russo, Serena Maria Boccia, Adriana Ionelia Apostol, Ilary Ruscito, Luca Romano, Christian Marth, Anna Fagotti, Francesca De Felice.

INTRODUCTION: Despite response to up-front treatment, patients with ovarian cancer remain at high risk of recurrence, with poor survival. Immunotherapy plus chemotherapy, alone or in combination with poly(ADP-ribose) polymerase inhibitors (PARPi) or VEGF inhibitors, has been investigated in ovarian cancer, with heterogeneous results.
METHODS: A meta-analysis of randomized phase III trials was conducted. PubMed, EMBASE, ClinicalTrials.gov, and congress proceedings were systematically searched. Two comparisons were performed: i) mono-immunotherapy throughout and the relative control arm; ii) immunotherapy plus PARPi and the relative control arm. The primary endpoint was the progression-free survival (PFS) and was analyzed in the overall population and by bevacizumab use, BRCA/homologous recombination deficiency (HRD) status, and PD-L1 expression.
RESULTS: Six trials, involving 6,465 patients, were analyzed. In the overall population, immunotherapy did not affect PFS, alone [Hazard ratio (HR) 0.94, 95% Confidence Interval (CI) 0.85-1.05] or with PARPi (HR 0.83, 95% CI 0.62-1.12). Potential benefits are suggested in selected populations. Immunotherapy plus PARPi and bevacizumab significantly improved PFS (HR 0.71, 95% CI 0.58-0.85). A PFS benefit was observed in the HRD-positive, BRCA wild-type and PD-L1-negative populations receiving immunotherapy plus PARPi (HR 0.71, 95% CI 0.52-0.97 and HR 0.72, 95% CI 0.57-0.91, respectively) compared to control groups. Mono-immunotherapy showed a slight advantage in HRD-negative patients (HR 0.87, 95% CI 0.78-0.98).
CONCLUSION: In first-line treatment of advanced ovarian cancer, immunotherapy ± PARPi does not provide PFS benefits in unselected patients. However, efficacy signals in specific subgroups support the need for biomarker-driven strategies and optimized trials.

Keywords: BRCA mutations; Bevacizumab; Homologous recombination deficiency; Immunotherapy; Ovarian cancer; PARP inhibitors; PD-L1 expression

DOI: https://doi.org/10.1016/j.critrevonc.2026.105383

Int J Gynecol Cancer. 2026 Apr 25. pii: S1048-891X(26)00260-4. [Epub ahead of print]36(7): 104729

Prognostic comparison of the FIGO 2009 and 2023 endometrial cancer staging systems: a large, single-institution retrospective cohort study.

Tiffany Y Sia, Qin Zhou, Sean Devlin, Alexia Iasonos, Sana Hatoum, Karen Haney, Sally Kraiem, Christian Dagher, Rofieda Alwaqfi, Eric Rios Doria, Britta Weigelt, Lora H Ellenson, Carol Aghajanian, Ying L Liu, Mario M Leitao, Nadeem R Abu-Rustum, Jennifer J Mueller.

OBJECTIVE: The International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system includes 21 sub-stages and proposes a shift from pure anatomical staging to an approach incorporating histology, grade, lymphovascular invasion, and molecular classification. We sought to evaluate the overall survival prognostic ability of the International Federation of Gynecology and Obstetrics 2023 endometrial cancer staging system compared with the International Federation of Gynecology and Obstetrics 2009 system.
METHODS: We collected clinicopathologic characteristics, molecular profiling results, and survival outcomes for all patients with a new diagnosis of endometrial cancer treated at our institution between 2016 and 2020. All cases underwent pathology review by a gynecologic pathologist at our institution. An International Federation of Gynecology and Obstetrics 2009 and 2023 stage was assigned. We applied R2ϵ statistics based on an isotonic proportional hazards model to compare prognostic ability between the 2 staging systems.
RESULTS: Of 2067 patients with endometrial cancer, 952 (46%) underwent tumor molecular profiling. When comparing International Federation of Gynecology and Obstetrics 2009 and 2023 staging, 538 (26.0%) patients were upstaged and 100 (4.8%) were downstaged in the 2023 system. Five-year overall survival estimates were similar across most stages between the 2 staging systems, with some exceptions: the International Federation of Gynecology and Obstetrics 2023 IA3 sub-stage demonstrated improved outcomes (100% vs 70.3% for International Federation of Gynecology and Obstetrics 2009 IIIA) and the IICmp53abn group had poorer prognosis (73% vs 86.8% for International Federation of Gynecology and Obstetrics 2009 II). Using isotonic proportional hazards regression models, the 2023 model slightly numerically outperformed the 2009 model for overall survival (R2ϵ 0.546 vs 0.415); however, adjusted 95% confidence intervals were under-developed.
CONCLUSIONS: Using a real-world, large, well-annotated cohort of patients with endometrial cancer with expert pathology review, we were able to calculate 5-year progression-free and overall survival rates for each sub-stage. The International Federation of Gynecology and Obstetrics 2023 model demonstrated slightly improved prognostic discrimination compared with the International Federation of Gynecology and Obstetrics 2009 model; however, small patient numbers in each sub-stage and concerns regarding over-fitting limit this analysis.

Keywords: Comparison; Endometrial Cancer; FIGO Staging; Outcomes

DOI: https://doi.org/10.1016/j.ijgc.2026.104729

Front Oncol. 2026 ;16 1759488

Application of a modified MSRE-qPCR method for detecting circulating cell-free DNA methylation in cervical cancer.

Yaru Liu, Tuping He, Shang Chen, Shenglong Wang, Zhihao Luo, Haixi Liu, Quan Liu, Dixian Luo.

Background: The methylation status of cell-free DNA (cfDNA) shows promise for the clinical detection of cervical cancer and its precursors; however, its measurement in liquid biopsies is hindered by low cfDNA yields and technically demanding protocols.
Methods: We developed an enhanced Methylation-sensitive restriction enzyme-quantitative polymerase chain reaction (MSRE-qPCR) method to create a combinatorial methylation assay with high sensitivity and specificity. Incorporating T4 DNA ligase following MSRE digestion improves the detection of short cfDNA fragments. This T4-assisted system enables methylation analysis of RXFP3-L1, RXFP3-L2, ZNF671, PAX1, and SOX1 for cervical cancer (CESC) evaluation with only 1.5 ng of DNA input; furthermore, lower input is sufficient for assessing the hypermethylated PAX1 gene.
Results: When applied to 24 blood samples from CESC patients and 21 matched tissues, the modified MSRE-qPCR method achieved 87.5% sensitivity and 90.3% specificity using 1.5ng of DNA, outperforming MethyLight without requiring more sensitive quantitative techniques. A methylation panel comprising RXFP3-L1, RXFP3-L2, ZNF671, and SOX1 yielded an AUC of 0.917 (95% CI: 0.830-1.000) in the development set. We constructed a logistic regression model using this gene panel to predict CESC status.
Conclusion: This methodological improvement overcomes the limitation of low cfDNA abundance and provides a practical methylation-based tool for CESC detection.
Clinical Significance: This non-invasive cfDNA methylation assay shows promise as an adjunct for the early detection of cervical cancer. It could also enhance screening adherence relative to conventional cytology, especially in resource-constrained environments.

Keywords: DNA methylation; MSRE-qPCR; Methylight; cell-free DNA; cervical cancer; cfDNA abundance; methylation panel

DOI: https://doi.org/10.3389/fonc.2026.1759488

bioRxiv. 2026 May 10. pii: 2026.04.29.721733. [Epub ahead of print]

Decoding the BRCA2 reversion principles underlying PARP inhibitor resistance.

Anna Gabrielle Horacek, Frances Li Kueper, Robert Lu, Isabella Paige Lamont, Stella Tran, Hanqin Li, Dirk Hockemeyer.

Reversion mutations that restore BRCA2 function represent a major mechanism of resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA2 -mutant cancers. Predicting these events could inform treatment strategies, identify patients at increased risk of acquiring PARPi resistance, and improve interpretation of secondary variants. Here, we use an isogenic cell system and CRISPR editing to define the principles governing BRCA2 reversion. We show that local sequence context dictates the spectrum of reversions, whereas domain architecture determines which events confer PARPi resistance. We characterize two routes of reversion that operate both within and across exons: DNA-level reading-frame restoration and transcript-level rescue via alternative splicing. Lastly, we identify distinct exon 11 reversion mechanisms, including large genomic deletions and recurrent splice isoforms predicted to remove all eight BRC repeats. These findings define a predictive code for BRCA2 reversion and PARPi resistance.

DOI: https://doi.org/10.64898/2026.04.29.721733

BMC Biol. 2026 May 21.

cyberDMR: accurate and robust identification of differentially methylated regions from WGS-derived methylomes.

Yang Li, Yadong Liu, Xian Chen, Weize Kong, Yadong Wang, Tao Jiang.

BACKGROUND: Differentially methylated regions (DMRs) are essential regulatory features for characterizing epigenetic variation, understanding population-level differences, and interpreting haplotype-specific methylation patterns. However, existing DMR detection methods often show unstable performance under biologically challenging scenarios such as sparse CpG regions, low sequencing depth, small sample sizes, extreme region lengths, and subtle methylation differences. These limitations highlight the need for a more robust and versatile approach capable of achieving accurate and consistent DMR detection across diverse genomic contexts. To address these challenges, we developed cyberDMR, a robust and noise-resilient DMR detection framework that integrates coverage-adaptive smoothing, seed-growing clustering, and weighted beta regression to achieve stable performance under whole-genome sequencing (WGS) and varying sequencing conditions.
RESULTS: cyberDMR consistently achieved the highest F1-scores on real WGBS prostate cancer datasets, outperforming other strong-performing methods by 2-18%. This advantage was further supported by extensive simulations spanning diverse genomic and experimental scenarios, in which cyberDMR maintained stable and leading performance, achieving a mean F1-score of 99.7% (± 0.3%) and consistently outperforming competing methods across diverse simulated settings. When applied to long-read methylation datasets, cyberDMR enabled the identification of 107 biologically meaningful methylation regions, including 15 gene-associated regions influenced by cis-acting methylation quantitative trait loci (meQTLs) and 2 corresponding putative novel imprinting candidates, ZNF714 and NINJ2.
CONCLUSIONS: cyberDMR provides a robust and accurate framework for genome-wide DMR detection, capturing consistent inter-group methylation differences while preserving intra-group consistency across diverse sequencing conditions.

Keywords: DMR detection; DNA methylation; Haplotype-based DMR; Low-coverage data; Population-based DMR

DOI: https://doi.org/10.1186/s12915-026-02634-3

Hum Mutat. 2026 ;2026 6909313

MLH1 Constitutional Epimutation Screening Requires Highly Sensitive Assays to Identify Lynch Syndrome Patients With Very Low Mosaic Methylation Level.

Constitutional epimutations of the MLH1 gene are an alternative cause of Lynch syndrome, in which inactivation of an allele of a mismatch repair (MMR) gene results from MLH1 promoter methylation, rather than a pathogenic genetic variant. These epimutations are often mosaic, and methylation levels ranging from ~50% monoallelic methylation to low-level methylation (1%-5%) are observed in the blood of MLH1 epimutation carriers. Using a specific and highly sensitive droplet digital methyl-specific PCR (ddMSP) assay, six patients with very low methylation levels (< 1%) were identified in a series of 142 patients with a MLH1-methylated tumor diagnosed before age 61, who had been referred to the clinical lab between 2020 and 2024. These patients were initially missed by standard pyrosequencing assay, emphasizing the need for highly sensitive assays for constitutional epimutation screening. To confirm that methylated DNA molecules detected by ddMSP did not correspond to circulating tumor DNA rather than germline DNA, multiple validation analyses were performed, including validation of the constitutional origin of methylation on other sources of germline DNA and tumoral analysis. Taking into account the other patients identified as epimutation carriers by pyrosequencing during the same 5-year period, 13.1% of patients with a MLH1-methylated tumor before age 61 were diagnosed as Lynch syndrome patients, which changed their clinical follow-up. These findings highlight the relevance of recommendations for systematic MLH1 epimutation screening using highly sensitive assays in patients with MLH1-methylated tumors diagnosed before age 61. Such screening will increase the number of patients diagnosed with Lynch syndrome caused by a MLH1 constitutional epimutation, improving patient care and outcomes, as well as genetic counseling.

Keywords: Lynch syndrome; MLH1 constitutional epimutation; MLH1-methylated tumors; mosaic promoter methylation; oncogenetics

DOI: https://doi.org/10.1155/humu/6909313