bims-ovdlit 2026-01-25 papers

Issue of 2026–01–25
six papers selected by
Lara Paracchini, Humanitas Research

Hered Cancer Clin Pract. 2026 Jan 17.

Decisional conflict in women with a BRCA1 or BRCA2 pathogenic variant who have not elected for risk-reducing salpingo-oophorectomy.

Kelly A Metcalfe, Anita Y Kinney, Steven A Narod, Aletta Poll, Susan Armel, Lucia Lombardi, Farideh Tavangar, Tuya Pal.

OBJECTIVE: To identify predictors of decisional conflict among women with a BRCA pathogenic variant (PV) who were eligible for risk reducing salpingo-oophorectomy (RRSO) who had not made a decision to have surgery at least one year after receiving genetic test results.
METHODS: Women with a BRCA1 or BRCA2 PV between the ages of 35 and 70 years old, who had not elected for RRSO at least 12 months after receipt of genetic test results, were administered self-report questionnaires investigating demographic variables, decisional conflict (Decisional Conflict Scale), cancer-related distress (Impact of Event Scale) and cancer risk perception. Decisional conflict scores were generated and a multivariable linear regression was conducted to identify variables associated with decisional conflict.
RESULTS: A sample of 107 women completed questionnaires. Overall, 44 participants (41%) had a high decisional conflict score (greater than 37.5) related to the RRSO decision. Higher education (β = 11.40, 95% C.I: 0.59, 22.20; p = 0.039), non-white race (β = 11.12, 95% C.I: 0.66, 21.57; p = 0.037), and having children (β = 22.89, 95% C.I: 10.07, 35.71; p < 0.001) were significantly associated with higher decisional conflict. Lower decisional conflict was significantly associated with genetic testing more than 3 years prior (β = -13.14, 95% C.I: -23.27, -2.99; p = 0.012).
CONCLUSIONS: Many women with a BRCA PV who have not elected for RRSO are experiencing high levels of decisional conflict related to the decision regarding RRSO. Interventions that target decisional conflict are needed to increase the uptake of RRSO which will result in a reduction of the risk of ovarian cancer in women with BRCA1 or BRCA2 PV.

Keywords: BRCA1; BRCA2; Bilateral salpingo-oophorectomy; Decisional conflict; Distress; Ovarian cancer; Risk

DOI: https://doi.org/10.1186/s13053-025-00329-4

J Liq Biopsy. 2026 Mar;11 100455

End-repair causes methylation underestimation in cell-free DNA sequencing libraries.

Tobin E Groth, Andrew A Mishin, Varsha Rao, Ruby Tibet, Christopher J Troll.

Cell-free DNA methylation sequencing provides insight into tissue of origin and chromatin structure. In some workflows, generating libraries includes end-repair. Using matched single-stranded and double-stranded libraries prepared from the same cfDNA extracts, we show that end-repair in double-stranded DNA libraries reduces globally inferred CpG methylation leading to decreased tissue of origin accuracy. Trimming read termini partially mitigates this bias but decreases coverage and removes fragmentomic information compared to single-stranded DNA libraries, which forego end-repair.

Keywords: Cell-free DNA (cfDNA); Double-stranded DNA (dsDNA) library preparation; End-repair; Fragmentomics; Methylation sequencing; Nucleosome positioning; Single-stranded DNA (ssDNA) library preparation; Tissue of origin (TOO)

DOI: https://doi.org/10.1016/j.jlb.2026.100455

J Insur Med. 2026 Jan 20.

When Is a Test Genetic? The Case of Multi-Cancer Early Detection Tests.

Timothy Meagher.

Multi-cancer early detection (MCED) tests are increasingly popular. Are these tests "genetic," and if so, can insurers use them in the risk assessment process? This article reviews definitions of genetic tests. It then reviews the motivation for limiting insurers' access to genetic tests and examines the wording in the legislation in 3 countries and 1 US state. It then attempts to establish whether MECD results are included in the legislation.

Keywords: Epigenetic test; Fragmentomics; Genetic Test; Germline testing; Hereditary genetic disorder; Metabolomics; Methylation patterns; Multi-cancer early detection test; Proteomics; Somatic testing

DOI: https://doi.org/10.17849/insm-53-1-1-4.2

Nat Genet. 2026 Jan 20.

The polygenic, omnigenic and stratagenic models of complex disease risk.

Judit García-González, Paul F O'Reilly.

A key goal of human genetics research is to understand how the effects of genetic variants combine to produce the risk of complex disease. Here we discuss and contrast three conceptual models developed to explain how multigenic risk is generated. The polygenic model, derived from the century-old infinitesimal model, has been the dominant framework for understanding the genetic inheritance of complex traits. More recently, two mechanistic models have been proposed: the omnigenic model, which hypothesizes core genes with direct effects on disease and peripheral genes with regulatory, indirect effects, and what we call the 'stratagenic' model, in which the genetic risk of disease is stratified across genomic pathways of functional relevance. There are key differences in the implications of these models for research, drug development and precision medicine. Therefore, it is essential to determine which model is most accurate for each disease or whether a single model is broadly optimal across complex diseases.

DOI: https://doi.org/10.1038/s41588-025-02467-w

Nat Commun. 2026 Jan 19. 17(1): 725

Integrative epigenetics and transcriptomics identify aging genes in human blood.

Mahdi Moqri, Kejun Ying, Jesse R Poganik, Chiara Herzog, Qingwen Chen, Mehrnoosh Emamifar, Alexander Tyshkovskiy, Alec Eames, Jure Mur, Dmitrii Glubokov, Benyamin Matei-Dediu, Ludger Goeminne, Wayne Mitchell, Daniel L McCartney, Lucas A Salas, Riccardo E Marioni, Jessica A Lasky-Su, Michael P Snyder, Vadim N Gladyshev.

Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these multi-omic aging genes in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation.

DOI: https://doi.org/10.1038/s41467-025-67369-1

Nat Commun. 2026 Jan 19. 17(1): 775

Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.

CZECANCA consortium

Loss-of-function variants in PALB2 give rise to defects in DNA damage repair by homologous recombination (HR), increasing the risk of breast cancer in female carriers. However, genetic testing frequently reveals missense variants of uncertain significance (VUS) for which the impact on protein function and cancer risk are unclear. Here we assay 84% of all possible missense variants in 11 out of 13 PALB2 exons using site-saturation functional screens with PARP inhibitor sensitivity as a readout for HR. These exons encode the coiled-coil and WD40 domains, which we identify as the minimal regions required for HR. Furthermore, we reveal the functional impact of 6718 missense variants, classifying 3904 variants as functional (58%), 2422 as intermediate (36%), and 392 as damaging (6%). A burden-type analysis shows that damaging missense variants in PALB2 are associated with a significantly increased risk of breast cancer, similar to that observed for truncating variants. These results will be valuable for the classification of PALB2 missense VUS and clinical management of carriers.

DOI: https://doi.org/10.1038/s41467-025-67252-z