bims-ovdlit 2025-08-31 papers

Nature. 2025 Aug 26.

Author Correction: Complex genetic variation in nearly complete human genomes.

Glennis A Logsdon, Peter Ebert, Peter A Audano, Mark Loftus, David Porubsky, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn A Paisie, William T Harvey, Xuefang Zhao, Gianni V Martino, Mir Henglin, Katherine M Munson, Keon Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, Stephan Scholz, Olanrewaju Austine-Orimoloye, Parithi Balachandran, Marc Jan Bonder, Haoyu Cheng, Zechen Chong, Jonathan Crabtree, Mark Gerstein, Lisbeth A Guethlein, Patrick Hasenfeld, Glenn Hickey, Kendra Hoekzema, Sarah E Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Youngjun Kwon, Chong Li, Heng Li, Jiaqi Li, Paul J Norman, Keisuke K Oshima, Benedict Paten, Adam M Phillippy, Nicholas R Pollock, Tobias Rausch, Mikko Rautiainen, Yuwei Song, Arda Söylev, Arvis Sulovari, Likhitha Surapaneni, Vasiliki Tsapalou, Weichen Zhou, Ying Zhou, Qihui Zhu, Michael C Zody, Ryan E Mills, Scott E Devine, Xinghua Shi, Michael E Talkowski, Mark J P Chaisson, Alexander T Dilthey, Miriam K Konkel, Jan O Korbel, Charles Lee, Christine R Beck, Evan E Eichler, Tobias Marschall.

DOI: https://doi.org/10.1038/s41586-025-09547-1

Proc Natl Acad Sci U S A. 2025 Aug 26. 122(34): e2426890122

Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.

PLATO-VTE Study Group

Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process-most likely inflammatory-from which abnormal fragmentation signatures are derived.

Keywords: autoimmune diseases; cancer screening; cell-free DNA; fragmentomics; rheumatology

DOI: https://doi.org/10.1073/pnas.2426890122

Nat Commun. 2025 Aug 26. 16(1): 7976

Peripheral blood DNA methylation predicts the early onset of primary tumor in TP53 mutation carriers.

Li-Fraumeni syndrome (LFS) confers high lifetime cancer risk due to germline TP53 pathogenic variants (PV). A comprehensive surveillance regimen termed the 'Toronto Protocol', has been adopted for early tumor detection, demonstrating improved survival among TP53 PV carriers. However, the protocol's "one-size-fits-all" approach fails to consider individual cancer risk. To personalize screening, we developed a support vector machine model to predict early onset of primary tumors (age < 6) using peripheral blood methylation data of TP53 PV carriers (n = 237). Validation (n = 64) and external testing (n = 79) showed AUROC = 0.928 [0.835-1.000], F1-score = 0.692 [0.435-0.867], and NPV = 0.984 [0.946-1.000]. The model achieved 91% accuracy, correctly classifying 90% of patients with cancer before the age of six and 87% of cancer-free individuals in the external test set. Our tool enables risk stratification for early-onset malignancies, to optimize clinical surveillance and improve patient outcomes.

DOI: https://doi.org/10.1038/s41467-025-62894-5

JAMA Oncol. 2025 Aug 21.

Personalized Primary and Secondary Prevention in Ovarian Cancer.

Martin Widschwendter, Adam N Rosenthal, Nora Pashayan, Louis Dubeau.

DOI: https://doi.org/10.1001/jamaoncol.2025.2873

ESMO Open. 2025 Aug 20. pii: S2059-7029(25)01410-3. [Epub ahead of print]10(9): 105541

Li Fraumeni syndrome in the UK: clinical characteristics and outcomes of TP53 carriers.

E Finn, S Sardo Infirri, C S Clarke, C Bunce, J Y Weng, R W Lee, Z Kemp, T P McVeigh, R Eeles, A George.

BACKGROUND: Li Fraumeni syndrome (LFS), a rare genetic condition, poses a significant health impact due to the ∼75%-90% lifetime risk of developing cancer in affected individuals. Due to the rarity of this disease, little is known about the outcomes, clinical characteristics, and treatments of cancer for patients with LFS.
PATIENTS AND METHODS: We present a retrospective dataset of 57 patients from 41 families diagnosed with LFS between 1996 and 2021, with or without a concurrent cancer diagnosis, who were managed at a single cancer institution in the UK. We present the cancer types that were observed in this group, the age at cancer diagnosis, and treatment modalities for those affected with cancer, either before or after having a TP53 test to establish their LFS diagnosis.
RESULTS: A total of 24 individuals underwent predictive testing, of which 13 were not diagnosed with cancer during the observation period. The other 33 individuals underwent diagnostic testing and had at least one cancer diagnosis each. Overall, there were 92 distinct cancer diagnoses in 44 participants, the majority being breast cancers and sarcomas. Patients were most likely to be diagnosed with LFS between the ages of 30 and 40 years. Some 75% of all cancer diagnoses were diagnosed at an early stage [TNM (tumour-node-metastasis) stage 0-2], and 19% had a recurrence, despite the early diagnosis. In total, 42% of individuals with LFS died as a result of a cancer diagnosis in our dataset, but the overall survival could not be calculated due to the short follow-up period (median 6 years, IQR 2-11 years).
CONCLUSIONS: Individuals with LFS have a high risk of cancer, cancer recurrence, and death. Larger multicentric international studies focusing on developing cohorts of specific diseases are needed to better understand disease patterns related to different pathogenic TP53 variants and inform which patients with LFS may need a more targeted and aggressive surveillance protocol.

Keywords: Li Fraumeni syndrome; breast cancer; early diagnosis; electronic patient record; sarcoma; screening; service evaluation

DOI: https://doi.org/10.1016/j.esmoop.2025.105541

Genes (Basel). 2025 Jul 27. pii: 883. [Epub ahead of print]16(8):

Does BRCA Mutation Status Influence Ovarian Cancer Onset Timing and Patients' Treatment Outcomes?

Kaja Michalczyk, Agata Mokrzycka, Marianna Rudzińska, Barbara Michalczyk, Janusz Menkiszak, Anita Chudecka-Głaz.

BACKGROUND/OBJECTIVES: Mutations in the BRCA1 and BRCA2 genes are well-known risk factors for ovarian cancer. They are also associated with response to platinum-based chemotherapy; however, their definitive impact on patient prognosis remains not fully understood. This study aimed to investigate the influence of BRCA mutation status on the age of ovarian cancer onset and on treatment outcomes in patients with high-grade serous ovarian cancer.
METHODS: This single-center retrospective analysis included newly diagnosed FIGO stage III and IV HGSOC patients treated between June 2018 and April 2023. Patients' age, tumor histology, CA125 levels, BRCA mutation status, type of treatment (neoadjuvant or adjuvant chemotherapy), and surgical outcomes were collected and analyzed. Survival analyses were performed using the Kaplan-Meier method and log-rank test.
RESULTS: Pathogenic mutations were identified in 25 patients (15 in BRCA1, 10 in BRCA2). Patients with a BRCA mutation were diagnosed at a significantly younger age (median 58.78 years) compared to non-carriers (66.81 years; p < 0.001), with BRCA1 carriers being diagnosed the youngest (median 46.52 years). The study found no statistically significant difference in progression-free survival (PFS) between BRCA carriers and non-carriers. However, a significant improvement in overall survival (OS) was observed for patients with a BRCA1 mutation (p = 0.036). No significant OS difference was found for BRCA2 carriers.
CONCLUSIONS: BRCA mutations, particularly in the BRCA1 gene, are associated with an earlier onset ovarian cancer. BRCA1 mutation appears to be a favorable prognostic factor for overall survival in patients with HGSOC. Our findings demonstrate the clinical implications of different BRCA mutations and support the need for further research in larger cohorts to confirm their influence on prognostic effects.

Keywords: BRCA1; BRCA2; HGSOC; ovarian cancer

DOI: https://doi.org/10.3390/genes16080883