bims-ovdlit 2025-06-01 papers

ESMO Open. 2025 May 29. pii: S2059-7029(25)01168-8. [Epub ahead of print]10(6): 105299

Response to letter re: Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study: Not all BRCA mutations are equal: functional context and mutation type as co-determinants of PARP inhibitor response.

DOI: https://doi.org/10.1016/j.esmoop.2025.105299

ESMO Open. 2025 May 29. pii: S2059-7029(25)01158-5. [Epub ahead of print]10(6): 105289

Response to letter re: Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study.

DOI: https://doi.org/10.1016/j.esmoop.2025.105289

Nat Med. 2025 May 27.

Early detection of multiple cancer types using multidimensional cell-free DNA fragmentomics.

The multicancer early detection (MCED) test has the potential to enhance current cancer-screening methods. We evaluated a new MCED test that analyzes plasma cell-free DNA using genetic- and fragmentomics-based features from whole-genome sequencing. The present study included an internal validation cohort of 3,021 patients with cancer and 3,370 noncancer controls, and an independent cohort of 677 patients with cancer and 687 noncancer individuals. The results demonstrated an overall sensitivity of 87.4%, specificity of 97.8% and tissue-of-origin prediction accuracy of 82.4% in the independent validation cohort. Preliminary results from a prospective study of 3,724 asymptomatic participants showed a sensitivity of 53.5% (predominantly early stage cancers) and specificity of 98.1%. These findings indicate that the MCED test has strong potential to improve early cancer detection and support clinical decision-making.

DOI: https://doi.org/10.1038/s41591-025-03735-2

Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00075-4. [Epub ahead of print]95 102537

Chromosomal instability in development and disease: Beyond cancer evolution.

Marco Milán.

Chromosomal instability (CIN), an increased rate of changes in chromosome structure and number, has been classically associated with human disease as a way of evolving the cancer genome. In recent years, three additional research lines concerning the impact of CIN on human disease have been consolidated. First, beyond the generation of genomic copy number heterogeneity, CIN acts as a source of tumor growth, metastasis, and malignancy through additional mechanisms. Second, CIN is pervasive in early human development, and the resulting aneuploid cells are selectively removed from the fetus to give rise to healthy births. Third, CIN is associated with mosaic variegated aneuploidy, a rare familial disease that compromises brain development and contributes to tumor formation. Here, I will review recent advances in these three topics, with a particular focus on the use of model systems and organisms to understand the increasing impact of CIN on human biology and disease.

DOI: https://doi.org/10.1016/j.ceb.2025.102537

Nat Methods. 2025 May 28.

SAVANA: reliable analysis of somatic structural variants and copy number aberrations using long-read sequencing.

Accurate detection of somatic structural variants (SVs) and somatic copy number aberrations (SCNAs) is critical to study the mutational processes underpinning cancer evolution. Here we describe SAVANA, an algorithm designed to detect somatic SVs and SCNAs at single-haplotype resolution and estimate tumor purity and ploidy using long-read sequencing data with or without a germline control sample. We also establish best practices for benchmarking SV detection algorithms across the entire genome in a data-driven manner using replication and read-backed phasing analysis. Through the analysis of matched Illumina and nanopore whole-genome sequencing data for 99 human tumor-normal pairs, we show that SAVANA has significantly higher sensitivity and 13- and 82-times-higher specificity than the second and third-best performing algorithms. Moreover, SVs reported by SAVANA are highly consistent with those detected using short-read sequencing. In summary, SAVANA enables the application of long-read sequencing to detect SVs and SCNAs reliably.

DOI: https://doi.org/10.1038/s41592-025-02708-0

Zhonghua Fu Chan Ke Za Zhi. 2025 May 25. 60(5): 372-382

[Association analysis on BRCA gene functional domain mutations and prognosis in patients with ovarian epithelial carcinoma and fallopian tube carcinoma].

M R Zhao, Y Q Yang, L Yu, L Zhang, Q J Chang, W W Cheng.

Objective: To analyze the characteristics of BRCA gene mutations in patients with ovarian epithelial carcinoma and fallopian tube carcinoma, and to investigate the impact of mutations in the functional domains of the BRCA genes on the prognosis of patients. Methods: This research collected a total of 273 patients diagnosed with primary ovarian epithelial carcinoma or fallopian tube carcinoma by pathological examination at the First Affiliated Hospital of Nanjing Medical University between January 2009 and December 2023.Data on their BRCA gene mutation status, clinicopathological data, and follow-up information were collected. A retrospective analysis was conducted to evaluate the association between BRCA gene mutations and patients' prognosis, including progression free survival (PFS) and overall survival (OS) time. Results: Among the 273 patients with ovarian or fallopian tube carcinoma, 101 cases (37.0%, 101/273) were positive for BRCA gene mutations (BRCA-positive group), while 172 cases (63.0%, 172/273) were negative for BRCA gene mutations (BRCA-negative group). (1) Clinicopathological characteristics: compared with the BRCA-negative group, the BRCA-positive group had a younger age at diagnosis, lower proportion of postmenopausal status, and lower recurrence rate (all P<0.05). Additionally, the BRCA-positive group showed a higher prevalence of family history of gynecological malignancies and a higher rate of no visible residual disease (R0) resection, all with statistical significance (all P<0.05). (2) Characteristics of BRCA gene mutations: among the 101 BRCA-positive patients, 74 cases (27.1%, 74/273) had BRCA1 gene mutations, 26 cases (9.5%, 26/273) had BRCA2 gene mutations, and 1 case (0.4%, 1/273) had indeterminate mutation records. According to the American College of Medical Genetics and Genomics (ACMG) 2015 guideline, mutations of uncertain significance accounted for 22.8% (23/101), likely pathogenic mutations accounted for 10.9% (11/101), and pathogenic mutations accounted for 59.4% (60/101), with 5.9% (6/101) unclassifiable. BRCA1 and BRCA2 genes have three (RING, DBD, BRCT) and two (RAD51-BD, DBD) major functional domains, respectively. Among the 89 BRCA-positive patients with detailed domain mutation data, the overall domain mutation rate was 40.4% (36/89), distributed as follows: DBD 14.6% (13/89), BRCT 12.4% (11/89), RING 4.5% (4/89), and RAD51-BD 9.0% (8/89). (3) Association between BRCA gene functional domain mutations and prognosis: among 77 patients with advanced stage (Ⅲ-Ⅳ) ovarian epithelial carcinoma in the BRCA-positive group with functional domain mutation data, the median PFS time was significantly longer in the 31 patients with domain mutations compared to the 46 patients with non-domain mutations (not reached during the follow-up period, vs 26.0 months; P=0.035). However, there was no significant difference in median OS time between the two groups (not reached during the follow-up period, vs 67.0 months; P=0.513). Median PFS time was longer in 13 patients with mutations in the DBD functional domain than that in 64 patients with mutations outside the DBD functional domain (not reached during the follow-up period, vs 28.0 months; P=0.042), whereas there was no significant difference in the comparison of median OS time between the two groups (not reached during the follow-up period, vs 67.0 months; P=0.321). (4) Association between BRCA gene functional domain mutations and efficacy of poly adenosine diphosphate ribose polymerase inhibitor (PARPi) maintenance therapy: among 51 advanced stage ovarian epithelial carcinoma patients who received PARPi maintenance therapy in the BRCA-positive group, 20 patients with domain mutations demonstrated significantly longer median PFS time compared to 31 patients with non-domain mutations (not reached during the follow-up period, vs 31.0 months; P=0.039). However, no significant difference was observed in median OS time between the two groups (not reached during the follow-up period, vs 53.0 months; P=0.178). PARPi maintenance therapy was more effective in the 9 patients with mutations in the DBD functional domain than that in the 42 patients with mutations located outside the DBD structural domain, with significant differences observed in both median PFS time (both not reached during the follow-up period; P=0.007) and median OS time (both not reached during the follow-up period; P=0.037). In contrast, patients with mutations in the BRCT or RAD51-BD domains showed no significant differences in either median PFS or OS time compared to patients with mutations outside these domains (all P>0.05). Conclusions: Patients with ovarian epithelial carcinoma and fallopian tube carcinoma who harbor BRCA functional domain mutations exhibit significantly longer median PFS time compared to those with non-domain mutations. Moreover, among patients received PARPi maintenance therapy, those with mutations in the DBD domain have a better median PFS and OS time benefit.

DOI: https://doi.org/10.3760/cma.j.cn112141-20250120-00030