bims-ovdlit 2025-01-12 papers

Issue of 2025–01–12
four papers selected by
Lara Paracchini, Humanitas Research

Cancer Res Commun. 2025 Jan 09.

Evaluating ovarian cancer risk-reducing salpingectomy acceptance: a survey.

Alexandra Lukey, Ramlogan Sowamber, David Huntsman, Celeste Leigh Pearce, A Fuchsia Howard, Rafael Meza, Michael R Law, Minh Tung Phung, Gillian E Hanley.

With evidence that salpingectomy is effective in preventing high grade serous carcinoma, it is time to consider offering this procedure to people at higher-than-average lifetime risk for ovarian cancer, despite not having a pathogenic genetic variant that increases risk for ovarian cancer. This targeted approach has potential to be effective at reducing ovarian cancer incidence, and unlike opportunistic salpingectomy is focused on people with an increased lifetime risk of ovarian cancer. However, the acceptability of this approach within the population of potential patients remains unknown. We conducted an online survey of adults in British Columbia, Canada, who were defined as "at risk" for ovarian cancer (i.e., people born with ovaries). Participants completed a questionnaire on demographics, ovarian cancer risk and protective factors, concerns about risk-reducing salpingectomy and the risk they considered high enough to warrant risk-reducing salpingectomy. We included 211 participants. Among these participants, 42% (n = 88) indicated they would consider risk-reducing salpingectomy at any lifetime risk or any risk above the population average. Another 20 participants chose risks between 1.5%- 4% for a cumulative 51% of the sample choosing risks below thresholds for oophorectomy. In contrast, 6% (n=12) indicated they would not consider the procedure at any risk level. None of the factors collected were associated with the likelihood that a person would find risk-reducing salpingectomy acceptable. Overall our participants showed broad interest in risk-reducing salpingectomy as an ovarian cancer prevention strategy. These results suggest there would likely be uptake if RRS was offered.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0566

Nat Commun. 2025 Jan 08. 16(1): 430

Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals.

Dimitrios V Vavoulis, Anthony Cutts, Nishita Thota, Jordan Brown, Robert Sugar, Antonio Rueda, Arman Ardalan, Kieran Howard, Flavia Matos Santo, Thippesh Sannasiddappa, Bronwen Miller, Stephen Ash, Yibin Liu, Chun-Xiao Song, Brian D Nicholson, Helene Dreau, Carolyn Tregidgo, Anna Schuh.

The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.

DOI: https://doi.org/10.1038/s41467-024-55428-y

Nature. 2025 Jan 08.

Functional evaluation and clinical classification of BRCA2 variants.

CARRIERS Consortium

Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers1-5. However, variants of uncertain significance limit the clinical utility of test results. Thus, there is a need for functional characterization and clinical classification of all BRCA2 variants to facilitate the clinical management of individuals with these variants. Here we analysed all possible single-nucleotide variants from exons 15 to 26 that encode the BRCA2 DNA-binding domain hotspot for pathogenic missense variants. To enable this, we used saturation genome editing CRISPR-Cas9-based knock-in endogenous targeting of human haploid HAP1 cells6. The assay was calibrated relative to nonsense and silent variants and was validated using pathogenic and benign standards from ClinVar and results from a homology-directed repair functional assay7. Variants (6,959 out of 6,960 evaluated) were assigned to seven categories of pathogenicity based on a VarCall Bayesian model8. Single-nucleotide variants that encode loss-of-function missense variants were associated with increased risks of breast cancer and ovarian cancer. The functional assay results were integrated into models from ClinGen, the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology9 for clinical classification of BRCA2 variants. Using this approach, 91% were classified as pathogenic or likely pathogenic or as benign or likely benign. These classified variants can be used to improve clinical management of individuals with a BRCA2 variant.

DOI: https://doi.org/10.1038/s41586-024-08388-8

Nat Rev Genet. 2025 Jan 09.

Epigenetics and individuality: from concepts to causality across timescales.

Amy K Webster, Patrick C Phillips.

Traditionally, differences among individuals have been divided into genetic and environmental causes. However, both types of variation can underlie regulatory changes in gene expression - that is, epigenetic changes - that persist across cell divisions (developmental differentiation) and even across generations (transgenerational inheritance). Increasingly, epigenetic variation among individuals is recognized as an important factor in human diseases and ageing. Moreover, non-genetic inheritance can lead to evolutionary changes within populations that differ from those expected by genetic inheritance alone. Despite its importance, causally linking epigenetic variation to phenotypic differences across individuals has proven difficult, particularly when epigenetic variation operates independently of genetic variation. New genomic approaches are providing unprecedented opportunity to measure and perturb epigenetic variation, helping to elucidate the role of epigenetic variation in mediating the genotype-phenotype map. Here, we review studies that have advanced our understanding of how epigenetic variation contributes to phenotypic differences between individuals within and across generations, and provide a unifying framework that allows historical and mechanistic perspectives to more fully inform one another.

DOI: https://doi.org/10.1038/s41576-024-00804-z