bims-ovdlit 2025-12-21 papers

Int J Gynecol Pathol. 2025 Nov 24.

Extensive Foamy Cell Change in Serous Tubal Intraepithelial Carcinoma and Tubal High-grade Serous Carcinoma.

High-grade serous carcinoma (HGSC) and its precursor, serous tubal intraepithelial carcinoma (STIC), usually exhibit cytologic features reminiscent of fallopian tube secretory cells, their presumed cell-of-origin. While it is not uncommon to encounter focal areas of cytoplasmic clearing in HGSC, we have occasionally observed extensive foamy change in STIC and tubal HGSC, which morphologically mimics mucinous differentiation, and to a lesser extent, clear cell carcinoma. In this report, we describe the histologic, immunophenotypic, and ultrastructural features of STIC/tubal HGSC with extensive foamy cell change. From 5 tubo-ovarian HGSC resections (chemotherapy-naive, n=4; post-neoadjuvant chemotherapy, n=1), STIC (n = 2), or tubal HGSC (n = 3) with extensive foamy cytoplasm were identified. Mucicarmine and Periodic acid Schiff/Alcian blue pH 2.5 stains were negative in the foamy cells, excluding mucin and glycogen accumulation. By immunohistochemistry, the tubal lesions retained Müllerian (tubal) differentiation (PAX8+, n=5; ER+, n=5; WT1+, n=4; PR+, n=3), along with aberrant p53 expression (n=5; concordant with somatic TP53 mutations detected by targeted next-generation sequencing). CDX2 and Napsin-A were absent, while HNF-1β and racemase showed variable staining. Adipophilin showed patchy expression in 2 cases, suggestive of lipid content. Ultrastructurally, foamy STIC/HGSCs contained numerous empty micro-vacuoles and macro-vacuoles, with occasional dilated rough endoplasmic reticulum. In contrast, fallopian tubes with true mucinous metaplasia (n=3) were highlighted by mucin stains and showed reduced or absent Müllerian marker expression. Foamy cell change is a distinctive cytoplasmic alteration in STIC and HGSC. The presence of this histologic feature should prompt immunohistochemical studies to confirm serous differentiation.

Keywords: Serous tubal intraepithelial carcinoma; fallopian tube; high-grade serous carcinoma; ovary

DOI: https://doi.org/10.1097/PGP.0000000000001151

Cancer Res. 2025 Dec 18.

Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions.

Tu-Yung Chang, Yen-Wei Chien, Szu-Hua Chen, Annelise Sokolow, Yeh Wang, Brant G Wang, Tricia A Numan, M Herman Chui, Rebecca L Stone, Thomas R Pisanic, Nickolas Papadopoulos, Tian-Li Wang, Christopher Douville, Leslie Cope, Ie-Ming Shih.

Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathological features in 166 ovarian precancerous lesions. Four pre-cancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline-BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double "two-hit" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive pre-cancerous lesions.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3189

NPJ Precis Oncol. 2025 Dec 15.

Improved circulating tumor DNA profiling by simultaneous extraction of DNA methylation and copy number information from methylated DNA sequencing data.

Daan M Hazelaar, Ruben G Boers, Joachim B Boers, Vanja de Weerd, Jean Helmijr, Maurice Phm Jansen, Henk Mw Verheul, Cornelis Verhoef, Joost Gribnau, John Wm Martens, Stavros Makrodimitris, Saskia M Wilting.

Cell-free DNA (cfDNA) analysis offers a powerful, minimally invasive approach to improve cancer care by measuring tumor-specific genomic and epigenetic alterations. Here, we demonstrate the versatility of MeD-seq, a methylation-dependent sequencing assay, for comprehensive cfDNA analysis, including DNA methylation profiling, chromosomal copy number (CN) alterations, and tumor fraction (TF) estimation. MeD-seq-derived CN profiles and TF estimates from 38 colorectal cancer patients with liver metastases (CRLM) and 5 ovarian cancer patients were highly comparable to shallow whole-genome sequencing (sWGS), validating our approach. For 120 CRLM patients, we used MeD-seq CN and TF information in an improved differential methylation model, which detected additional significantly Differentially Methylated Regions (DMRs) correlating with TF estimates. Using the identified DMR sets, we were subsequently able to distinguish healthy blood donors from CRLM patients with low amounts of circulating tumor DNA (ctDNA) as well. These findings establish MeD-seq as an affordable platform for tumor-agnostic detection of cancer-specific signals in plasma. This methodological framework provides a foundation for clinical applications requiring sensitive ctDNA detection from limited sample material, including treatment response assessment and minimal residual disease monitoring.

DOI: https://doi.org/10.1038/s41698-025-01237-5

EBioMedicine. 2025 Dec 16. pii: S2352-3964(25)00531-6. [Epub ahead of print]123 106081

Combining cell-free DNA fragmentomes and total tumour volume improves prognostication and tumour response evaluation in patients with colorectal cancer liver metastases.

BACKGROUND: Treatment decisions in patients with unresectable colorectal liver metastases (CRLM) are largely guided by radiological response to induction systemic therapy. However, radiological assessment alone provides an imprecise estimate of underlying tumour biology or treatment response. Circulating tumour DNA (ctDNA) is an emerging biomarker that can support clinical decision-making. This study evaluated the independent prognostic value of radiological tumour burden and DELFI-TF, a tumour tissue- and mutation-independent cell-free DNA (cfDNA) fragmentome-based ctDNA assay.
METHODS: We analysed 202 plasma samples and CT scans collected at baseline and following induction systemic therapy from 101 patients with unresectable, liver-limited CRC enrolled in the phase-III CAIRO5 trial (NCT02162563), treated with FOLFOX/FOLFIRI plus bevacizumab. Total tumour volume (TTV) was centrally quantified via semi-automated segmentation of liver metastases. ctDNA was measured using the DELFI-TF score. Associations with overall survival (OS) and early recurrence were evaluated using multivariable Cox regression models.
FINDINGS: At baseline, TTV (median = 139 mL, IQR = 23-497 mL) strongly correlated with DELFI-TF (median = 0.29, IQR = 0.13-0.41; Spearman's ρ = 0.70). DELFI-TF showed a more pronounced reduction than TTV on-treatment (-97.6% vs -49.9%). Baseline levels and on-treatment changes of DELFI-TF (P = 0.001; P = 0.012) and TTV (P = 0.002; P = 0.002) were independently associated with OS in the multivariable model; their combination improved prognostic performance (Uno's C-statistic 0.78 vs 0.73; P = 0.036). Baseline (P = 0.016) and on-treatment DELFI-TF (P = 0.001) also predicted early recurrence after local therapy.
INTERPRETATION: Following further validation, integrating cfDNA fragmentome-based testing with radiological tumour volume may provide complementary and clinically meaningful insights for prognostication and treatment response in patients with unresectable CRLM. This exploratory study supports a multimodal biomarker approach to guide personalised treatment strategies.
FUNDING: German Research Foundation (DFG, 513004649), Heidelberg Medical Faculty, Dutch Cancer Society/KWF Kankerbestrijding (10438), PPP Allowance via Health ∼ Holland (LSHM22027), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer (SU2C)in-Time Lung Cancer Interception Dream Team Grant, SU2C-Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415), Gray Foundation, Commonwealth Foundation, Cole Foundation, Delfi Diagnostics (research grant), US National Institutes of Health (CA121113, CA233259, CA271896).

Keywords: Cell-free DNA fragmentome; Colorectal liver metastases; Liquid biopsies; Prognosis; Risk stratification; Total tumour volume; Treatment response

DOI: https://doi.org/10.1016/j.ebiom.2025.106081

Int J Cancer. 2025 Dec 16.

Challenges in the future of cancer screening.

Future of Cancer Screening Working Group

The purpose of cancer screening is to reduce mortality, and ideally incidence, from the cancer screened for. Until recently, cancer screening has been offered to all persons in pre-defined sex- and age-groups. The exception is lung screening which is targeted to high-risk individuals. Evidence for effect of screening on cancer-specific mortality is available for cancer of the cervix, breast, colorectal, lung, and prostate, and on cancer-specific incidence for cervix and colorectal cancer. With more effective molecular and computational tools, the current paradigm of cancer screening will change. Manual reading of images and pathology in mammography, cytology, colposcopy, colonoscopy, and CT scan will be complemented or replaced by AI-interpretation. Risk stratification will diversify screening intensity, for instance in breast screening where modelling and randomized controlled trials are underway. Blood-based screening tests might allow for simultaneous early detection of several types of cancer. Furthermore, prediction models based on life trajectories in health and other data will enhance risk stratification, potentially dividing the population into groups with no need of screening, with need of simple or advanced screening, with need of surveillance or even diagnostics. In public health care systems, these developments must be closely monitored. Before replacing an existing program, evidence for non-inferiority in reducing cancer-specific mortality should be ensured. Benefits must outweigh harms, and citizens should have confidence in new screening schemes. With the pressure on health care resources, screening should continue in organized and monitored programs. Taking these conditions into account, the new screening tools will potentially enable improved cancer control.

Keywords: cancer; evidence; screening

DOI: https://doi.org/10.1002/ijc.70286

Gynecol Oncol. 2025 Dec 17. pii: S0090-8258(25)01129-1. [Epub ahead of print]204 251-253

ASCO neoadjuvant chemotherapy in ovarian cancer guideline: A SGO endorsement.

Jamie Lesnock, Stéphanie Gaillard, William P Tew.

DOI: https://doi.org/10.1016/j.ygyno.2025.12.004

Fam Cancer. 2025 Dec 18. 25(1): 5

Functional characterization of splice variants in hereditary breast and ovarian cancer susceptibility genes.

Keywords: BRCA ; CHEK2 ; TP53 ; Breast/ovarian cancer susceptibility genes; Splicing; Variant classification

DOI: https://doi.org/10.1007/s10689-025-00521-4

J Natl Cancer Inst. 2025 Dec 13. pii: djaf349. [Epub ahead of print]

Cancer risks in lynch syndrome carriers: a systematic review and meta-analysis.

Séphora Campoy, Youenn Drouet, Pauline Rochefort, Valérie Bonadona, Christine Lasset.

BACKGROUND: Lynch Syndrome (LS), caused by pathogenic variants (PVs) in mismatch repair (MMR) genes, increases the risk of several cancers. Surveillance guidelines vary internationally due to inconsistent risk estimates. This study refines cancer risk estimates by gene, sex, and age to support personalized recommendations.
METHODS: This meta-analysis included studies reporting cumulative cancer risks in genetically confirmed LS PV carriers. PubMed was searched until December 31, 2024. Following the MOOSE guideline, data were extracted independently by two reviewers and analyzed using fixed (n = 2 estimates) or random-effects models (n > 2 estimates), stratified by gene, sex, cancer site, and study design LS retrospective family studies (LSRF), LS prospective cohort (LSPC), and population-based case-control (PBCC).
RESULTS: Thirty-three studies were included, mostly LSRF. Meta-analysis of LSRF showed that colorectal cancer risk by age 40 was markedly lower in MSH6 and PMS2 carriers (<2%) than in MLH1 and MSH2 (>4%). For endometrial cancer, risks at 50 y were 8.3%[5.1-13.4], 8.7%[3.8-18.7], 5.2%[2.3-11.2] and 3.0%[1.0-8.0] for MLH1, MSH2, MSH6 and PMS2 respectively. For ovarian cancer, risks at 40 y were 1.2%[0.6-2.7] and 0.9%[0.5-1.8] for MLH1 and MSH2, respectively. Few studies addressed other cancer types, highlighting the need for additional data.
CONCLUSIONS: This is the first meta-analysis providing stratified cancer risk estimates by cancer site, gene, and study design. These findings support gene-specific surveillance strategies, such as initiating colonoscopy at age 30-35 for MSH6 and PMS2 carriers, postponing hysterectomy after 50 y for PMS2 carriers, and delaying oophorectomy after 45 y for MLH1 and MSH2 PV carriers.

Keywords: Cancer risk; Genetic epidemiology; Lynch Syndrome; Oncogenetics

DOI: https://doi.org/10.1093/jnci/djaf349