bims-ovdlit 2025-09-14 papers

Issue of 2025–09–14
nine papers selected by
Lara Paracchini, Humanitas Research

Gynecol Oncol. 2025 Sep 11. pii: S0090-8258(25)00980-1. [Epub ahead of print]201 223-234

Risk of melanoma among people with BRCA1 and BRCA2 pathogenic variants: A systematic review and meta-analysis.

Nicole M Frontera, Muhammad Danyal Ahsan, Isabelle R Chandler, Sarah R Levi, Jesse T Brewer, Jessica M Weiss, Xiaoyue Ma, Sarah T Jewell, Ravi N Sharaf, Melissa K Frey.

BACKGROUND: Patients with BRCA1/2 pathogenic gene variants (PGVs) have an increased risk for breast, ovarian, pancreatic, and prostate cancer, with emerging evidence suggesting an association with melanoma. We aim to evaluate the strength of the melanoma association to guide cancer risk-management recommendations.
METHODS: This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42024519298). Key electronic databases were searched to identify studies evaluating the association of melanoma with germline BRCA1/2 PGV status. Data from eligible studies were meta-analyzed.
RESULTS: Thirty-nine studies were included in this review. Among 7142 patients with melanoma, the pooled prevalence of BRCA1/2 PGVs was 1.7 % (95 % CI 1.1 % - 2.6 %). Among 2340 patients with melanoma compared to 116,501 controls, the pooled odds ratio (OR) of having a BRCA1/2 PGV was 2.8 (95 % CI 1.5-5.4), with similar ORs for BRCA1 (3.2 [95 % CI 1.6-6.3]) and BRCA2 (2.8 [95 % CI 1.2-6.6]) independently. Of 14,293 BRCA1/2 PGV carriers, 1.3 % (95 % CI 0.9-1.8) developed melanoma. The risk of melanoma among 11,154 BRCA1 PGV carriers was not different to that among 11,553 controls (OR 1.0 [95 % CI 0.3-3.6]), with insufficient data to meta-analyze risk for BRCA2.
CONCLUSIONS: Our meta-analysis demonstrates that individuals with melanoma have a pooled OR of 2.84 for carrying a BRCA1 or BRCA2 PGV compared to controls; however, limited data suggest no difference in the relative risk of developing melanoma among BRCA1 PGV carriers compared to controls, with insufficient data for relative risk with BRCA2 PGV. These results suggest that although BRCA1/2 PGVs may be associated with melanoma, the magnitude of increased risk is likely relatively low. Well-designed cohort studies are warranted to further investigate the magnitude of melanoma risk among BRCA1/2 PGV carriers and providers should consider this potential risk when counseling patients.

Keywords: BRCA1; BRCA2; Hereditary breast and ovarian cancer; Melanoma

DOI: https://doi.org/10.1016/j.ygyno.2025.08.030

Cancer Control. 2025 Jan-Dec;32:32 10732748251378666

Alleviating the Global Burden of Cancer Through Prevention and Early Detection.

Iffat Elbarazi, Luai A Ahmed.

This editorial introduces the "Cancer Control" Special Collection featuring 14 peer-reviewed diverse studies from diverse geographical regions and thematic areas, including screening, HPV vaccination, cancer literacy, genetic and molecular innovations, and culturally tailored interventions. This collection highlights disparities in access, uptake, and awareness across populations emphasizing the urgent need for evidence-based strategies. It calls for integrated approaches in prevention, health education, policy reform, and technological advancements to reduce the global cancer burden, which continues to rise, especially in low- and middle-income countries.

Keywords: awareness; cancer burden; cancer prevention; early detection; special collection

DOI: https://doi.org/10.1177/10732748251378666

Cytopathology. 2025 Sep 11.

Cytological and Immunocytochemistry Findings in Fallopian Tube Brush Specimens and Their Correlation With Histology.

Jitka Hausnerová, Robert Slunečko, Petra Ovesná, Markéta Bednaříková, Lenka Zlámalíková, Jan Kosťun, Petr Stráník, Vendula Smoligová, Libor Viktora, Michaela Koblížková, Jiří Presl, Vít Weinberger.

CONTEXT: High-grade serous carcinoma (HGSC), the most prevalent and lethal form of ovarian cancer, is increasingly recognised to originate in the fimbrial end of the fallopian tube (FT). Timely detection remains a critical unmet clinical need due to ineffective screening methods. This prospective observational study assesses the diagnostic potential of FT brush cytology by correlating cytomorphological and immunocytochemical findings with histologically confirmed HGSC.
METHODS AND MATERIAL: A total of 134 FT from 89 patients undergoing salpingo-oophorectomy (with or without hysterectomy) were analysed. Liquid-based cytology samples were evaluated for morphological abnormalities and subjected to immunocytochemistry using p53 and Ki-67 markers. Cytological results were classified as benign, suspicious or malignant. Statistical analyses included sensitivity, specificity and odds ratio calculations via logistic regression (α = 0.05), performed using the R software.
RESULTS: Histopathology confirmed HGSC in 15 patients. Of these, brush cytology identified 12 as suspicious or malignant, demonstrating high diagnostic concordance. Aberrant p53 expression was found in 11 cases, and a high Ki-67 proliferation index was observed in 10. These findings underscore the strong correlation between cytological, immunocytochemical and histological features of tubal HGSC.
CONCLUSIONS: In conclusion, FT brush cytology combined with p53 and Ki-67 immunocytochemistry shows promise as a minimally invasive approach for early HGSC detection. Future research should focus on larger prospective cohorts, ideally incorporating in vivo hysteroscopic sampling.

Keywords: brush cytology; fallopian tube; high‐grade serous carcinoma; immunocytochemistry

DOI: https://doi.org/10.1111/cyt.70022

Nat Rev Cancer. 2025 Sep 08.

Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.

Hariharan Easwaran, Ashani T Weeraratna.

Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50-60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.

DOI: https://doi.org/10.1038/s41568-025-00868-x

Lancet Oncol. 2025 Sep 05. pii: S1470-2045(25)00379-1. [Epub ahead of print]

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): 10-year clinical outcomes and post-hoc analysis by molecular classification from a randomised phase 3 trial.

BACKGROUND: The PORTEC-3 trial investigated the benefit of chemoradiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We present the preplanned long-term analysis of the randomised PORTEC-3 trial with a post-hoc analysis including molecular classification of the tumours.
METHODS: PORTEC-3 was an open-label, multicentre, randomised, international phase 3 trial. Women were eligible if they had high-risk endometrial cancer (either International Federation of Gynecology and Obstetrics 2009 stage I, grade 3, with deep myometrial invasion and/or lymphovascular space invasion; stage II-III; or stage I-III with serous or clear-cell histology), were aged 18 years or older, and had a WHO performance score of 0-2. Participants were randomly assigned (1:1) to receive pelvic radiotherapy (48·6 Gy in 1·8 Gy fractions) or chemoradiotherapy (radiotherapy combined with two cycles of cisplatin 50 mg/m2 intravenously in weeks one and four, followed by four cycles of carboplatin area-under-the-curve 5 and paclitaxel 175 mg/m2 intravenously at 3-week intervals). Randomisation was done by use of biased-coin minimisation with stratification for participating centre, lymphadenectomy, stage, and histological type. We report the primary outcomes of overall survival and recurrence-free survival at 10 years. We also report primary outcomes by molecular subgroup in a post-hoc analysis. Survival was analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov (NCT00411138) and is now complete.
FINDINGS: Between Nov 23, 2006, and Dec 20, 2013, 660 eligible and evaluable patients recruited at 103 centres in six clinical trial groups across seven countries were randomly assigned to chemoradiotherapy (n=330) or radiotherapy alone (n=330). Median follow-up was 10·1 years (IQR 9·8-11·0). Estimated 10-year overall survival was 74·4% (95% CI 69·8-79·4) in the chemoradiotherapy group and 67·3% (62·3-72·7) in the radiotherapy group (adjusted hazard ratio [HR] 0·73 [95% CI 0·54-0·97], p=0·032), and 10-year recurrence-free survival was 72·8% (67·2-77·6) versus 67·4% (61·7-72·4; adjusted HR 0·74 [95% CI 0·56-0·98], p=0·034). Molecular analysis was available for 411 (62%) patients (210 [64%] of 330 patients in the chemoradiotherapy group and 201 [61%] of 330 patients in the radiotherapy group), whose characteristics were similar to the overall trial population. Post-hoc analysis by molecular class showed that, for women with p53 abnormal tumours, 10-year overall survival was 52·7% (95% CI 40·8-68·1) with chemoradiotherapy versus 36·6% (25·0 to 53·7) with radiotherapy alone (adjusted HR 0·52 [95% CI 0·30-0·91], p=0·021); 10-year recurrence-free survival was 52·6% (95% CI 38·3 to 65·0) versus 37·0% (95% CI 23·7 to 50·2; HR 0·42 [95% CI 0·24 to 0·74], p=0·0027). MMRd and POLEmut cancers did not seem to benefit from chemoradiotherapy over radiotherapy alone, whereas the effects for NSMP cancers were modulated by oestrogen-receptor status.
INTERPRETATION: 10-year overall survival and recurrence-free survival were improved for patients with high-risk endometrial cancer treated with adjuvant chemoradiotherapy versus radiotherapy alone, with most clinically relevant benefit suggested for p53 abnormal cancers.
FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Australia, Cancer Australia, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

DOI: https://doi.org/10.1016/S1470-2045(25)00379-1

Cell Rep Methods. 2025 Jul 21. pii: S2667-2375(25)00119-5. [Epub ahead of print]5(7): 101083

Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection.

Yunze Wang, Yuying Hou, Zhankun Xiong, Libo Lu, Zhanxiang Zong, Bo Wang, Hebing Chen, Wen Zhang, Xionghui Zhou.

We introduce a cell-free DNA (cfDNA) fragmentation pattern: the fragment dispersity index (FDI), which integrates information on the distribution of cfDNA fragment ends with the variation in fragment coverage, enabling precise characterization of chromatin accessibility in specific regions. The FDI shows a strong correlation with chromatin accessibility and gene expression, and regions with high FDI are enriched in active regulatory elements. Using whole-genome cfDNA data from five datasets, we developed and validated the FDI-oncology model, which demonstrates robust performance in early cancer diagnosis, subtyping, and prognosis. Case studies reveal that key cancer genes such as HER2 and TP53 exhibit significantly different FDIs between cancer and control samples. Simulation experiments suggest that deep targeted sequencing of a small number of regions can achieve high diagnostic efficiency.

Keywords: CP: cancer biology; CP: systems biology; cancer early detection; cfDNA; liquid biopsy; machine learning

DOI: https://doi.org/10.1016/j.crmeth.2025.101083

Cancer Sci. 2025 Sep 12.

DNA Methylation in Ovarian and Endometrial Cancers: Predictive and Mechanistic Roles in PARP Inhibitor and ICI Response.

Shuhei Kitamura, Ayumi Taguchi, Kana Tamai, Yoko Yamamoto, Anh Quynh Duong, Daisuke Yoshimoto, Ayako Mori, Aya Ishizaka, Saki Tsuchimochi, Kenbun Sone, Masahito Kawazu, Katsutoshi Oda, Yasushi Hirota.

Cancer treatment is shifting from an organ-based approach to one driven by biological phenotypes, emphasizing the need to understand molecular mechanisms. DNA methylation plays a pivotal role in tumor biology, not only through gene silencing but also by inducing distinct behaviors beyond genetic mutations. In gynecologic cancers, molecular diagnostics, such as homologous recombination deficiency status guiding poly(ADP-ribose) polymerase (PARP) inhibitor therapy in ovarian cancer and deficient mismatch repair/microsatellite instability-high status informing immune checkpoint inhibitor (ICI) therapy in endometrial cancer have already been used in clinical practice. However, tumors with epigenetically driven functional deficiencies, such as BRCA1 promoter methylation in homologous recombination-deficient ovarian cancers or MLH1 promoter methylation in deficient mismatch repair/microsatellite instability-high endometrial cancers, often exhibit poorer prognoses and reduced therapeutic responses compared to their genetically mutated counterparts. Given the unique impact of DNA methylation, precise detection is crucial. Integrating methylation analysis into molecular classification could refine diagnostics-both by identifying mechanistic contributors to treatment response and by serving as predictive biomarkers for therapy selection-thereby optimizing patient management. This review explores the role of DNA methylation in modulating responses to PARP inhibitors and ICIs, highlights its promise as a biomarker in precision oncology, and outlines current developments and clinical challenges in BRCA1 and MLH1 methylation assays.

Keywords: BRCA1 ; MLH1 ; DNA methylation; PARP inhibitors; immune checkpoint inhibitors

DOI: https://doi.org/10.1111/cas.70189

Nature. 2025 Sep 10.

Fluctuating DNA methylation tracks cancer evolution at clinical scale.

Cancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour.

DOI: https://doi.org/10.1038/s41586-025-09374-4