bims-ovdlit 2026-05-10 papers

Nat Commun. 2026 May 08.

Cell-free DNA size deconvolution resolves nucleosomal origins and reveals tumor-associated fragmentomic alterations.

Ze Zhou, Wendy N Cooper, Zhao Cheng, Sara Lightowlers, Charlotte E Coles, Amit Roshan, Nitzan Rosenfeld, Hui Zhao.

Analysis of cell-free DNA (cfDNA) fragmentomic features holds great promise for minimally invasive cancer diagnostics. Although selectively analyzing short plasma cfDNA enriches tumor-derived DNA (ctDNA), the mechanisms shaping cfDNA size profiles remain incompletely understood. Here, we develop a generalized model of cfDNA fragment length distributions across multiple bodily fluids (saliva, urine, cerebrospinal fluid, lymphatic fluid, and plasma), deconvoluting size profiles into ~10-bp periodic peaks (components), each approximated by a Cauchy-Lorentz distribution. This analytical framework enables investigation of cfDNA fragmentation across diverse pathological states and reveals a 159-bp component that may demarcate intra- and inter-nucleosomal cfDNA. By analyzing plasma DNA from individuals harboring germline TP53 mutations, patients receiving radiotherapy, and liver transplantation recipients, we demonstrate that ctDNA shortening can be distinguished from phagocytosis-associated cfDNA shortening through differences in the amplitude and scale parameters of intra- and inter-nucleosomal components. Moreover, leveraging tumor-related fragmentomic alterations, characterized by increased fragmentation entropy identified through cfDNA size deconvolution, significantly enhances cancer detection.

DOI: https://doi.org/10.1038/s41467-026-72925-4

Eur J Cancer. 2026 Apr 15. pii: S0959-8049(26)00520-4. [Epub ahead of print]240 116739

ESGO Consensus Statement on endometrial cancer prevention, risk reduction strategies, and management of women with Lynch syndrome.

Lynch syndrome (LS) is a hereditary condition associated with an increased susceptibility to developing cancer, primarily colorectal and gynaecological cancer (endometrial cancer and ovarian cancer). The European Society of Gynaecological Oncology (ESGO) nominated fifteen practicing multidisciplinary clinicians with expertise in this field and ten gynaecological and oncological fellows with interest in the topics to develop evidence-based statements, sharing and standardizing the management of LS carriers. Published evidence was integrated with clinical experience to reach Consensus Statements through anonymous voting. In this Consensus, thirty-one statements based on the best available evidence and expert agreement are offered. They focused on genetic and cancer risk counseling principles, screening procedures, risk-reducing surgical and medical strategies, and address emerging topics such as reproductive issues for LS carriers, which are important in current practice. This manuscript reports the Statements that reached a consensus, their voting results, and a summary of supporting evidence.

Keywords: Endometrial cancer; Lynch Syndrome; Ovarian cancer; Risk-reducing strategy; Screening

DOI: https://doi.org/10.1016/j.ejca.2026.116739

Obstet Gynecol. 2026 May 07.

Hereditary Breast and Ovarian Cancer: Overview of Gene-Specific Risks and Challenges in Genetics Care Delivery.

Ying L Liu, Varshini Gali, Melissa K Frey.

Breast and ovarian cancers are major public health challenges, with rising breast cancer incidence and persistently high ovarian cancer mortality. Approximately 10% of breast cancers and up to 25% of ovarian cancers are attributable to germline pathogenic variants (also called mutations) in cancer susceptibility genes, most notably BRCA1/2, but several other genes also contribute to risk of ovarian and breast cancers. Identification of pathogenic variants enables targeted prevention and early detection strategies, including enhanced surveillance and risk-reducing surgery, which can significantly decrease cancer incidence, morbidity, and mortality. We seek to review the specific risks of breast and ovarian cancer-associated genes and management strategies. Advances in sequencing technology, reduced sequencing costs, and legislative protections against genetic discrimination have expanded access to genetic testing, and clinical guidelines have broadened the pool of individuals recommended for testing. Despite these advances, most individuals with hereditary cancer syndromes remain undiagnosed, limiting the reach of precision cancer prevention. Underutilization of genetic testing is particularly pronounced among underserved populations, perpetuating disparities in health outcomes. Emerging health care delivery models have improved uptake and reduced barriers and can be considered for integration into obstetrics and gynecology practices. Ongoing research into the fallopian tube origin of high-grade serous ovarian cancer has prompted research that may expand risk-reducing surgical options. Collectively, these innovations mark a transformative era in hereditary cancer care, emphasizing access, multidisciplinary integration, and the urgent need for novel delivery models to ensure that the benefits of genetic testing reach all individuals at risk.

DOI: https://doi.org/10.1097/AOG.0000000000006304

bioRxiv. 2026 Apr 21. pii: 2026.04.17.718766. [Epub ahead of print]

Tissue-Specific Prevalence and Clonal Architecture of BRCA1/2 LOH-Inducing Chromosomal Aneuploidy.

Xinfeng Wang, Saumya D Sisoudiya, Mahad Bihie, Yves Greatti, Julián Grandvallet Contreras, Tomi W Jun, Smruthy Sivakumar, Kuan-Lin Huang.

Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome arms 17q and 13q-harboring the BRCA1 and BRCA2 genes, respectively-relative to other solid tumor types, and that mutational timing analysis independently places these deletions among the earliest somatic events in these cancers. Phylogenetic reconstruction of single-cell data reveals that in pre-malignant breast tissue from germline BRCA1/2 carriers, chr17q and chr13q deletions appear as localized subclonal events within small clades against a largely diploid background. In established malignancies, these same deletions are found within dominant clonal lineages accompanied by widespread genomic instability-consistent with clonal sweeps originating from early deletion events. These findings suggest that breast and ovarian cellular environments confer a selective advantage for chr17q and chr13q deletions, providing a mechanism that may contribute to the tissue-specific cancer risk observed in gBRCA1/2 carriers.

DOI: https://doi.org/10.64898/2026.04.17.718766

Gynecol Oncol. 2026 May 07. pii: S0090-8258(26)01971-2. [Epub ahead of print]209 56-61

Risk-reducing gynecologic surgery decisions in Lynch syndrome at a safety-net hospital and university medical center.

Rebecca M Waggoner, Charité N Ricker, Qi Nie, X Mona Guo, Jacob G Comeaux, Emmeline Y Chang, Natalia Gutierrez, Daisy Hernandez, Averi Nguyen, Ivan Garcia, Fumito Ito, Laurie L Brunette, Lynda D Roman, Darcy Spicer, Julie O Culver.

OBJECTIVE: To explore uptake of risk-reducing gynecologic surgery in a diverse patient population with Lynch syndrome.
METHODS: Chart reviews of women with Lynch syndrome were conducted at a safety-net hospital and university medical center, including women over age 30 with an intact uterus and/or ovaries and no prior history of uterine or ovarian cancer. Potential factors associated with uptake of surgery and time to risk-reducing surgery were analyzed.
RESULTS: The 65 women studied included 27 (41.5%) White, non-Hispanic, 30 (46.2%) Hispanic, 5 (7.7%) Asian, and 3 (4.6%) other. The diagnosis of Lynch syndrome was made at a median of 41.0 years (IQR 31.0 to 48.0) with pathogenic variants in MLH1 (27, 41.5%), MSH2 (14, 21.5%), MSH6 (5, 7.7%), PMS2 (17, 26.2%), or EPCAM (2, 3.1%). The majority (35, 53.8%) had a history of colon or other cancer, and 24 (36.9%) were Spanish-language preferring. Safety-net hospital patients were more likely to undergo risk-reducing surgery (19/28, 67.9%) compared to university medical center patients (13/37, 35.1%), even when controlling for age and prior history of non-gynecologic cancer (HR = 2.43, p = 0.02). Safety-net hospital patients also demonstrated quicker uptake of surgery (p = 0.005). Age, parity, Lynch-associated gene, benign gynecologic diagnosis, family history, race/ethnicity, or language preference were not significantly associated with undergoing surgery.
CONCLUSION: This exploratory analysis suggested a higher uptake of risk-reducing surgery at the safety-net hospital than at the university medical center. Understanding factors contributing to this difference will be critical to supporting gynecologic cancer risk management in Lynch syndrome.

Keywords: Decision-making; Gynecologic cancer; Lynch syndrome; Risk-reduction; Surveillance

DOI: https://doi.org/10.1016/j.ygyno.2026.04.017

Surg Pathol Clin. 2026 Jun;pii: S1875-9181(26)00006-1. [Epub ahead of print]19(2): 333-345

The Molecular Landscape of Ovarian Neoplasms: A Review.

Amir Momeni-Boroujeni, Rajmohan Murali.

This article summarizes the molecular landscape of epithelial and non-epithelial ovarian tumors, integrating current genomic and immunophenotypic data. High-grade serous carcinomas are defined by TP53 and homologous recombination defects, while low-grade serous, mucinous, endometrioid, and clear cell carcinomas exhibit pathway-specific mutations such as MAPK/MEK and PI3K/AKT pathway alterations. Sex cord-stromal tumors are characterized by FOXL2, DICER1, and CTNNB1 alterations. The article also outlines hereditary cancer syndromes affecting ovarian tumorigenesis, emphasizing tumor predisposition associated with BRCA1/2, Lynch syndrome, Peutz-Jeghers syndrome, and DICER1.

Keywords: Homologous recombination deficiency; Molecular pathology; Ovarian carcinoma; Ovarian sex cord stromal tumor; TP53

DOI: https://doi.org/10.1016/j.path.2026.01.006

JAMA. 2026 May 08.

These Blood Tests May Detect Dozens of Cancers, but Will They Save Lives?

Rita Rubin.

DOI: https://doi.org/10.1001/jama.2026.4742

Haematologica. 2026 May 01. 111(5): 1532-1535

Introduction to the Review Series. Clonal hematopoiesis review series - from biology to clinical management.

Anastasija A Piric, Aaron D Schimmer.

DOI: https://doi.org/10.3324/haematol.2025.288295

Int J Gynecol Cancer. 2026 Apr 09. pii: S1048-891X(26)00221-5. [Epub ahead of print] 104690

Homologous recombination-deficient high-grade serous ovarian cancers exhibit distinct morphological features.

OBJECTIVE: Access to homologous recombination testing remains limited in many centers. We aim to correlate the morphology and immunophenotype of high-grade serous ovarian carcinoma with homologous recombination statuses.
METHODS: A retrospective analysis of a high-grade serous ovarian carcinoma tumors with known homologous recombination status. A pathological review of morphology was performed for each tumor, along with immunohistochemical profiling. Tumor morphology was classified as (1) solid, pseudo-endometrioid, or transitional (2) micropapillary or nested.
RESULTS: Overall, 81 tumors were included. The median age was 62 (interquartile range; 52-71). Of those, 27 (33.3%) tumors were BRCA1mut, 19 (23.5%) were BRCA2mut, 15 (18.5%) tumors had no BRCA1 or BRCA2 mutations but exhibited a genomic instability score ≥42 and were classified as BRCA1/2-wild-type with homologous recombinant deficient. The remainder 20 (24.7%) cases were homologous recombinant proficient. The proportion of tumors with solid transitional-like morphology was higher in BRCA1 (12/21, 57%) and BRCA2 (12/18, 67%) compared to the tumors with homologous recombinant proficient (3/17, 18%), p =.019. When stratified by genomic instability score, tumors with low score (genomic instability score <26) exhibited 0% solid transitional-like morphology versus 43% solid transitional-like morphology in high-score (genomic instability score >26), p =.03. PAX8 diffuse expression was detected in 71% of BRCA1, 65% of BRCA2, 92% of BRCA-wild-type homologous recombinant deficient tumors, and 100% of homologous recombinant proficient tumors, p =.071. The proportion of diffuse expression was higher in homologous recombinant proficient (100%) versus BRCA2 (65%) (Bonferroni-adjusted pairwise comparisons).
CONCLUSIONS: Homologous recombinant deficient tumors are associated with the solid transitional-like morphology, with the BRCA1/2-mutated homologous recombinant deficient cases showing the strongest correlation. Genomic instability score alone may not fully capture the spectrum of homologous recombinant deficient-related phenotypes. The variation in solid transitional-like morphology features among BRCA1- or BRCA2-mutated, BRCA1/2- wild-type with homologous recombinant deficient, and homologous recombinant proficient cases may reflect the diverse biological spectrum of different homologous recombination alterations.

Keywords: BRCA1/BRCA2; High-Grade Serous Ovarian Carcinoma; Homologous Recombination Deficiency; Immunohistochemistry; SET Morphology

DOI: https://doi.org/10.1016/j.ijgc.2026.104690

Nat Rev Drug Discov. 2026 May 08.

The ovarian cancer drug market.

Anna Duran-Corbera, Rachel M Webster.

DOI: https://doi.org/10.1038/d41573-026-00077-7