bims-ovdlit 2025-04-20 papers

Issue of 2025–04–20
six papers selected by
Lara Paracchini, Humanitas Research

Int J Gynaecol Obstet. 2025 Apr 15.

Pathology results of risk-reducing salpingo-oophorectomy in BRCA1/2 carriers and long-term clinical outcomes.

Wisam Assaf, Amalfi Qarawani, Yousef Abboud, Eiman Shalabna, Chen Nahshon, Ariel Zilberlicht, Ari Reiss, Meirav Schmidt, Yakir Segev.

INTRODUCTION: BRCA1/2 mutation carriers have a lifetime ovarian cancer risk of 40%-45% for BRCA1 and 15%-20% for BRCA2. The most effective risk-reduction strategy for women with known BRCA mutations remains bilateral risk-reducing salpingo-oophorectomy (RRSO), which reduces the risk by 80%. The primary objective of this study is to assess the long-term incidence of primary peritoneal carcinoma (PPC) following RRSO and to evaluate the occurrence of premalignant and malignant lesions.
METHODS: This retrospective cohort study followed BRCA1/2-positive patients who underwent RRSO, using data from two medical centers in Haifa Israel between 2002 and 2023. Data collected included demographic characteristics and pathology results post-surgery. Outcomes included rates of occult cancer (OC), serous tubal intraepithelial carcinoma (STIC), and PPC.
RESULTS: A total of 214 women underwent RRSO. Of these, 126 (58.8%) had a BRCA1 mutation, 76 (35.5%) had a BRCA2 mutation, and 12 (5.6%) carried both BRCA1 and BRCA2 mutations. During a mean follow-up of 122.4 months (SD ± 84.0), three patients (1.5%) developed PPC. OC was identified in 13 patients (6.1%) during RRSO. Out of the 13 OC patients, eight (61.5%) were classified as stage 1. The overall survival for the OC population was 117.2 ± 55.9 months. STIC was detected in two patients.
CONCLUSION: In this large retrospective analysis of BRCA carriers who underwent RRSO, we confirmed that long-term follow-up is crucial for BRCA mutation carriers undergoing RRSO, as malignancies can still arise over time. In our study, the incidence of PPC was 1.5%, highlighting the need for extended surveillance. These findings underscore the importance of meticulous surgical protocols, expert pathology review, and ongoing monitoring to optimize patient outcomes.

Keywords: BRCA; STIC; occult cancer; peritoneal cancer; risk reduction

DOI: https://doi.org/10.1002/ijgo.70110

STAR Protoc. 2025 Apr 11. pii: S2666-1667(25)00163-7. [Epub ahead of print]6(2): 103757

Protocol for the analysis of cell-free DNA end characteristics for accurate cancer diagnosis.

Xiaoyi Liu, Fanglei Gong, Huizhen Lin, Yunyun An, Kun Sun.

Fragmentation patterns of plasma cell-free DNA (cfDNA) are promising biomarkers in cancer diagnosis. Here, we present a protocol to enrich tumor-derived cfDNA molecules through end selection. We describe steps for installing software, aligning plasma cfDNA data to the reference genome, and performing end selection on cfDNA. We then detail procedures for building cancer diagnostic models with artificial intelligence. Overall, we provide commands to align cfDNA whole-genome sequencing data starting from raw reads, then extract fragmentomic features, and finally build diagnostic models with performance evaluations. For complete information on the generation and use of this protocol, please refer to Ju et al.1.

Keywords: Cancer; Genomics; Sequence analysis

DOI: https://doi.org/10.1016/j.xpro.2025.103757

Genome Res. 2025 Apr 14. 35(4): 572-582

Evolution of genome-wide methylation profiling technologies.

Carolina Montano, Winston Timp.

In this mini-review, we explore the advancements in genome-wide DNA methylation profiling, tracing the evolution from traditional methods such as methylation arrays and whole-genome bisulfite sequencing to the cutting-edge single-molecule profiling enabled by long-read sequencing (LRS) technologies. We highlight how LRS is transforming clinical and translational research, particularly by its ability to simultaneously measure genetic and epigenetic information, providing a more comprehensive understanding of complex disease mechanisms. We discuss current challenges and future directions in the field, emphasizing the need for innovative computational tools and robust, reproducible approaches to fully harness the capabilities of LRS in molecular diagnostics.

DOI: https://doi.org/10.1101/gr.278407.123

Clin Cancer Res. 2025 Apr 14.

A Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer ("PREDICT") - Baseline findings for CA125.

Rudolf Kaaks, Victoria Cooley, Trasias Mukama, Lauren R Teras, Alpa V Patel, Giovanna Masala, Marta Crous-Bou, Holly R Harris, Hilde Langseth, Heljä-Marja Surcel, Nicolas Wentzensen, Kathryn Terry, Naoko Sasamoto, Shelley Tworoger, Renée Turzanski Fortner.

PURPOSE: Epithelial ovarian cancer (EOC) is a lethal malignancy. CA125, the "best" available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by "omics" technologies. Discovery studies for EOC biomarkers should be conducted in pre-diagnosis blood samples from prospective cohorts to maximize likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage, while reducing methodologic biases.
EXPERIMENTAL DESIGN: Individual cohorts with pre-diagnosis blood samples have insufficient sample size for such studies. thus, we established "PREDICT" ("Prospective Early Detection Consortium for Ovarian Cancer")-a collaboration of nine prospective studies-to assemble a sufficient number of EOC cases with blood samples collected ≤18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay.
RESULTS: The discrimination capacity for single CA125 measurements in samples collected <6 months prior to diagnosis was high (area under the curve (AUC), PREDICT overall=0.92; range across cohorts of non-pregnant individuals=0.89-0.98), and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed.
CONCLUSIONS: Ongoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and microRNAs, using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multi-modal screening, as a complement to CA125 and combined with imaging.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1845

Gynecol Oncol. 2025 Apr 17. pii: S0090-8258(25)00152-0. [Epub ahead of print]197 1-10

TP53 somatic evolution in the normal endometrium of Black and White individuals.

Eric Rios-Doria, Elizabeth U Parker, Brendan F Kohrn, Mindy Pike, Coohleen Coombes, Elena Latorre-Esteves, Daniel J Reiter, Jeanne Fredrickson, Ronit Katz, Elizabeth M Swisher, Kemi M Doll, Rosa Ana Risques.

BACKGROUND: TP53 mutations are the main drivers of aggressive, high-risk endometrial carcinomas commonly diagnosed in Black individuals. However, TP53 mutations have also been identified in benign, non-cancerous tissues. We sought to understand the TP53 mutational landscape in benign endometrium throughout the lifespan of Black and White individuals, accounting for structural socioeconomic context.
METHODS: Ultra-sensitive TP53 mutation detection was performed with high-depth duplex sequencing (∼13,000×) in DNA extracted from histologically normal endometrium collected at autopsy (69 % of cases) or surgery (31 % of cases) from 83 individuals ages 0 to 81 (31 Black and 52 White, median age 35 years) without endometrial cancer. Histologically normal endometrium was also collected from 10 White individuals with endometrial cancer.
RESULTS: We identified 266 coding TP53 mutations in the normal endometrium of individuals without endometrial cancer, 57 % of which were pathogenic. The number, pathogenicity, and size of TP53 mutant clones in normal endometrium increased with age. Multivariable models showed no significant association between race or socioeconomic metrics and TP53 mutation frequency in normal endometrium. An exploratory analysis on the histologically normal endometrium of White individuals with endometrial cancer identified the tumor mutations at low levels in the normal biopsy of 5 out of 6 cases.
CONCLUSIONS: Our study revealed prevalent TP53 somatic evolution in benign endometrium across human lifespan and no racial differences in this cohort of predominantly younger individuals. Future studies should consider the analysis of larger cohorts with older individuals to detect potential effects of racial disparities on TP53 somatic evolution later in life.

Keywords: Clonal evolution; Clonal expansions; Endometrial cancer; Racial disparities; Somatic evolution; TP53

DOI: https://doi.org/10.1016/j.ygyno.2025.04.002

Int J Gynecol Cancer. 2024 Jun;pii: S1048-891X(24)01430-0. [Epub ahead of print]34(6): 964

Cancer statistics, 2024: mixed results in gynecologic oncology.

Elvio Silva.

Keywords: Cervical Cancer; Endometrium; Ovarian Cancer

DOI: https://doi.org/10.1136/ijgc-2024-005457