bims-ovdlit 2025-02-16 papers

Int J Gynecol Cancer. 2025 Jan 13. pii: S1048-891X(25)00148-3. [Epub ahead of print]35(2): 101635

Oral contraceptive use is associated with a reduction in the physical size of fallopian tube p53 signatures.

Evan Gibbard, Dawn R Cochrane, Ramlogan Sowamber, Jutta Huvila, Amanda S Nitschke, Kendall Greening, Christine Chow, Yimei Qin, Nissreen Mohammad, David Farnell, Wren S Lee, C Blake Gilks, Lien Hoang, Gillian E Hanley, David G Huntsman.

OBJECTIVE: Oral contraceptives reduce ovarian cancer risk, but the mechanism of risk reduction is not understood. We examined whether oral contraceptive pill (OCP) use influences p53 signatures, which are putative early fallopian tube precursors for high-grade serous ovarian carcinomas.
METHODS: For this retrospective cohort (n = 250) of subjects aged over 50 years who had fallopian tubes removed at the time of a benign gynecologic procedure, we used health records to identify 72 patients who used OCPs for at least 5 years and 178 subjects with no history of OCP use. Immunohistochemistry for p53 was performed on all fallopian tube sections, with 8 individuals removed for lack of identifiable tissue. p53 Signatures were identified and stratified based on size. Logistic regressions were run to estimate the association between OCP use and p53 lesion and lesion size.
RESULTS: There was no difference in the occurrence of p53 lesions with 20 of 70 of OCP users (28.6%) and 57 of 172 of those with no history of OCP use (33.1%). Subjects who used OCPs were more likely to have a small lesion (OR 1.98, 95% CI 1.03 to 3.83) and had decreased risk of having a medium/large lesion (OR 0.38, 95% CI 0.18 to 0.79). A total of 2 serous tubal intraepithelial lesions and 2 serous tubal intraepithelial carcinomas were identified in OCP-naive patients, whereas none were found in those with a history of OCP use.
CONCLUSIONS: OCP exposure was associated with a shift toward smaller p53 lesion size but was not found to be associated with a difference in the number of p53 lesions between OCP-exposed and unexposed patients. Future research should examine whether OCP use reduces proliferation and clonal expansion of p53 signature lesions toward higher risk precursors and, eventually, cancer. There were no serous tubal intraepithelial lesions and serous tubal intraepithelial carcinomas in patients with OCP exposure.

Keywords: Fallopian Tube Neoplasms; Oral Contraceptives; Ovarian Cancer; Ovarian Cancer Precursors

DOI: https://doi.org/10.1016/j.ijgc.2025.101635

Int J Gynecol Cancer. 2025 Jan 23. pii: S1048-891X(25)00187-2. [Epub ahead of print]35(2): 101662

High-grade serous ovarian cancer-bridging the gap between epidemiology and prevention with biology.

Smadar Bauer, Amit Oza, Stephanie Lheureux.

DOI: https://doi.org/10.1016/j.ijgc.2025.101662

Int J Cancer. 2025 Feb 12.

DNA methylation and copy number alterations in the progression of HPV-associated high-grade vulvar intraepithelial lesion.

Flavia Runello, Aude Jary, Sylvia Duin, Yongsoo Kim, Kahren van Eer, Féline O Voss, Nikki B Thuijs, Maaike C G Bleeker, Renske D M Steenbergen.

Human papillomavirus (HPV)-associated high-grade vulvar intraepithelial lesion (HSIL) is a precursor of vulvar squamous cell carcinoma (VSCC). Because of the 8% cancer risk, many vulvar HSIL patients undergo aggressive and mutilating treatments. Characterizing HSIL by their progression risk can help individualize treatment strategies. Accordingly, copy number alterations (CNAs) and DNA methylation have been identified as biomarkers for cancer risk stratification of HSIL. Here, we assessed their potential correlation, and relation to HPV16 (sub)lineages and progression to vulvar cancer. Eighty-two vulvar formalin-fixed paraffin-embedded (FFPE) samples, including controls, HSIL, HSIL adjacent to VSCC and VSCC, with previously determined DNA methylation profiles, were analysed for CNAs using mFAST-SeqS. Genome-wide z-scores were calculated to determine overall aneuploidy (aneuploidy scores), and compared to the methylation levels and status of marker panel ZNF582/SST/miR124-2. For 52 HPV16-positive cases, HPV (sub)lineages were determined by Sanger sequencing. HPV16 lineage A was predominant (86.4%), followed equally by lineages B, C, and D. Frequent chromosomal alterations included chr1pq, chr3q, chr9q gains, and chr2q, chr4q losses. Median aneuploidy scores increased across disease categories, from 0 in controls, to 3 in HSIL, 16 in HSIL adjacent to VSCC and 29 in VSCC. A positive relationship between aneuploidy scores and DNA methylation levels was found (ρ = 0.61, Spearman's rank correlation test). Aneuploidy scores were significantly higher in methylation-positive samples (p < .001). In conclusion, we showed that DNA methylation and CNAs both rise with increasing severity of disease, indicating their prognostic value for cancer risk stratification of HSIL, while no relation to HPV16 (sub)lineages was found.

Keywords: DNA methylation; copy number alterations; high‐grade vulvar intraepithelial lesion; mFAST‐SeqS

DOI: https://doi.org/10.1002/ijc.35366

Clin Cancer Res. 2025 Feb 11.

Characterization of plasma cell-free DNA variants as of tumor- or clonal hematopoiesis-origin in 16,812 advanced cancer patients.

PURPOSE: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based Comprehensive Genomic Profiling (CGP). However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.
EXPERIMENTAL DESIGN: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole exome and whole transcriptome NGS workflow that independently sequences both plasma-derived cell-free total nucleic acids (cfTNA) as well as the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.
RESULTS: 42.3% of 16,812 patients presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% NRAS, 5.8% BRAF, 2.1% EGFR, 2.1% KRAS, and 18.5% TP53. For patients aged 65-69, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70-74, 33% for ages 75-79, and 50% for ages 80+. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.
CONCLUSION: This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3335