Tag: Academic research

A study carried out in Estonia on healthy relatives of breast and ovarian cancer patients shows around 20% of those tested carried some form of genetic variant that increased their risk of developing cancer.

The study showed that BRCA1/2 cancer-associated variants, currently the most widely recognized and tested cancer predisposition genes overall, accounted for 58.4% of all pathogenic variants uncovered by the investigators, but 41.6% were in non-BRCA genes.

“A carrier rate of 19.7% is remarkably high compared with the general population and strongly supports broader and more systematic genetic testing of relatives in families affected by breast and ovarian cancer,” lead investigator Mikk Tooming, PhD, a researcher at the Institute of Clinical Medicine in Tartu, Estonia, told Inside Precision Medicine.

“The highest yield was observed when a pathogenic variant was already known in the family… However, even among relatives without a previously identified familial variant, 8% carried a pathogenic variant. This is a clinically meaningful detection rate and suggests that genetic testing should not be restricted only to families in which a specific variant has already been identified.”

The current study, published in Frontiers in Genetics, included 3,472 healthy family members of people with breast and ovarian cancer. Of these individuals, 88% were female and 12% male. Most of those tested (79%) were younger than 51 years, which is when cancer screening often starts.

The researchers retrospectively analyzed genetic results from the family members, tested at four hospitals between 2007 and 2023. Testing evolved from targeted Sanger sequencing and microarrays in the early years to broad multigene next generation screening panels covering up to 6,700 genes by 2023.

Overall, around 20% of the tested family members carried a pathogenic or likely pathogenic variant. This went up to 41.8% when a familial variant was already known, versus 8.0% when it was not. BRCA1/2 variants accounted for most variants, but 23 genes were implicated in total, with CHEK2, ATM, BRIP1, and PALB2 also prominent.

Notably, the youngest group tested, those who were 30 years or younger, were more likely to have a cancer risk variant than older groups with a rate of 28%. “Age is highly relevant because many hereditary cancer syndromes begin to confer increased cancer risk well before routine screening starts,” says Tooming. “Identifying carriers early allows surveillance and prevention plans to be implemented at the most appropriate time.”

Despite being under tested, the carrier rate of risk variants in the men tested was high at 34%. Breast and ovarian cancers are thought of as predominantly female conditions. While women may be more impacted by these cancers than men, men can also carry relevant risk variants and these can increase their risk of developing other cancers.

“Both healthcare providers and families may focus testing efforts on women, unintentionally overlooking men,” emphasizes Tooming. “This highlights a significant gap in current practice. Male carriers, particularly those with BRCA2 variants, have elevated risks of prostate cancer, male breast cancer, pancreatic cancer, and several other malignancies. Health systems should actively promote genetic counselling and testing for male relatives when hereditary cancer risk is suspected.”

The researchers support expanded testing but believe that earlier and more personalized genetic risk assessment, for example, in families known to be impacted by cancer, would produce better results than simply lowering the age of cancer screening.

“The data suggest that individuals from families affected by breast and ovarian cancer should undergo earlier evaluation for hereditary cancer risk. When a pathogenic variant is identified, surveillance should be tailored according to the specific gene and associated cancer risk,” says Tooming.

“While our study did not include longitudinal follow-up and therefore cannot directly measure reductions in cancer incidence or mortality, the high proportion of carriers identified before standard screening age strongly suggests that expanded testing has the potential to deliver substantial public health benefits in Estonia and elsewhere.”

The post <i>BRCA</i> Tests Alone Miss 42% of Hereditary Cancer Risk appeared first on Inside Precision Medicine.

A comprehensive multi-omics analysis published in Nature Medicine provides new mechanistic insights into extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts, advancing understanding of the molecular and cellular interactions that will shape the clinical translation of xenogeneic liver support.

The study builds on a previously reported first-in-human decedent model in which blood from four brain-dead human recipients was circulated through ten-gene-edited porcine livers for up to 84 hours. While the initial work demonstrated that ELC could provide meaningful metabolic support, significant thrombocytopenia and evidence of host immune activation remained major barriers. The new study applies longitudinal, species-resolved multi-omics to dissect these biological responses at unprecedented resolution.

Researchers from NYU Langone Health, NYU Grossman School of Medicine, and the Perelman School of Medicine at the University of Pennsylvania profiled 64 serial blood samples using proteomics, metabolomics, and lipidomics alongside spatial transcriptomic analysis of 25 porcine liver biopsies and three native human liver samples. This integrated approach enabled simultaneous tracking of human and porcine molecular signatures throughout the xenoperfusion procedures.

Spatial transcriptomics revealed progressive infiltration of human innate immune cells into the porcine xenografts, dominated by inflammatory macrophages and neutrophils. These infiltrating cells expressed pro-inflammatory cytokines including IL1B, TNF, and IL6, while resident porcine Kupffer-like macrophages and T cells declined over time. Adaptive immune cell infiltration remained comparatively limited, suggesting that the extensive genetic engineering of the donor pigs may mitigate early adaptive rejection during short-term support.

One of the study’s most important findings was the distinct behavior of the human and porcine complement systems. While human complement proteins declined during ELC, the pig liver continued producing high levels of complement components C3 and C5 alongside acute-phase proteins and coagulation factors. The findings suggest that the xenograft actively drives innate immune and inflammatory responses rather than simply replacing liver function. Because currently available complement inhibitors are designed to target human proteins, they may not adequately suppress pig-derived complement activity, highlighting a potential need for species-specific therapeutics and additional genetic engineering to improve xenograft compatibility.

The investigators also identified candidate mechanisms underlying the profound thrombocytopenia consistently observed during ELC. Human platelets rapidly accumulated within the porcine liver, where they colocalized with activated sinusoidal endothelial cells expressing increasing levels of porcine von Willebrand factor (vWF), as well as infiltrating macrophages, neutrophils, and hepatocytes. Elevated expression of platelet adhesion receptors and evidence of platelet activation, aggregation, and phagocytosis point to a multifactorial process involving endothelial activation, innate immune responses, and platelet clearance pathways. These findings nominate multiple potential therapeutic targets, including porcine-specific vWF interactions and complement-mediated inflammatory signaling.

Beyond immune compatibility, the multi-omics analyses demonstrated sustained hepatic metabolic activity throughout the procedures. The xenografts supported bilirubin clearance, amino acid metabolism, detoxification, and synthesis of albumin, transferrin, apolipoproteins, and coagulation factors. In one recipient who underwent hepatectomy, the extracorporeal pig liver maintained critical metabolic functions for more than 48 hours in the absence of a native liver, although circulating lipid levels remained reduced during exclusive xenograft support.

The study also illustrates the growing value of systems biology approaches in transplantation research. By integrating longitudinal proteomic, metabolomic, lipidomic, and spatial transcriptomic datasets, investigators were able to distinguish donor- and recipient-derived biological processes while identifying dynamic molecular networks that would likely remain undetected using conventional analyses.

Although the cohort comprised only five ELC procedures in four decedents, it represents the most comprehensive molecular characterization of pig-to-human liver xenoperfusion reported to date. The findings provide a roadmap for improving xenograft biocompatibility through both genetic engineering and targeted therapeutics, while establishing species-resolved multi-omics as a powerful platform for biomarker discovery and mechanism-driven optimization of xenotransplantation strategies.

The post Human-Pig Interactions in Liver Xenotransplant Recipients: A Multi-Omics Study appeared first on Inside Precision Medicine.