Atallah, A. | bioRxiv Science

bioRxiv2025

Mosaicism of BRAF V600E in Healthy Skin Predicts Neurodegeneration in Histiocytosis

Most histiocytoses harbor an oncogenic somatic alteration activating the MAP kinase pathway, the most frequent of which is BRAFV600E. Targeted therapy with BRAF or MEK inhibitors is highly effective, but neurodegeneration remains a severe complication. Recent data suggest that neurodegeneration may be secondary to mosaicism for BRAFV600E in microglia. In the prospective observational TARGET-HISTIO cohort study, we investigated extra-CNS mosaicism of BRAFV600E in a cohort of 124 adults with histiocytosis. Seeking widespread mosaicism, we analyzed healthy skin biopsies from areas without histiocytosis or melanocytic infiltration using high-sensitivity digital polymerase chain reaction. BRAFV600Ewas detected in healthy skin in 57/67 (85%) patients with BRAFV600Ehistiocytosis and was present in all second and third skin biopsies (n=6). BRAFV600Ewas absent from skin biopsies in all 37 patients with histiocytosis harboring another oncogenic mutation. BRAFV600E was also present in skin biopsies of four /20 patients with histiocytosis of unknown molecular status. Cells harboring BRAFV600E share characteristics with resident dermis macrophages. Only 58% of patients with BRAFV600E in skin also had BRAFV600E in blood leukocytes. Variant allele frequency in skin and blood leukocytes was 16 times lower than in histiocytosis, and frequency in skin was independent of treatment with BRAF/MEK inhibitors. None of the patients with wild type BRAF alleles in skin had neurodegeneration, whereas 22/61 (36%) of patients with BRAFV600E in skin had neurodegeneration. This study demonstrates that mosaicism of BRAFV600Ein healthy skin is frequent in patients with histiocytosis and is strongly associated with neurodegeneration. Key PointsLow allele frequency of the oncogene BRAF V600E is frequent in healthy skin of patients with histiocytosis. Patients without BRAF V600E in skin do not develop neurodegeneration, while 36% of those with BRAF V600E mosaicism do.

cancer biology↗

bioRxiv2021

Transgenerational impact of aberrant inflammation in rat pregnancy

Children of women with pre-eclampsia have increased risk of cardiovascular (CV) and metabolic disease in adult life. Furthermore, the risk of pregnancy complications is higher in daughters born to women affected by pre-eclampsia than in daughters born after uncomplicated pregnancies. While aberrant inflammation contributes to the pathophysiology of pregnancy complications, including pre-eclampsia, the contribution of maternal inflammation to subsequent risk of CV and metabolic disease as well as pregnancy complications in the offspring remains unclear. Here we demonstrate that 24-week-old female rats (F1) born to dams (F0) exposed to lipopolysaccharide (LPS) during pregnancy (to induce inflammation) exhibited mild systolic dysfunction, increased cardiac growth-related gene expression, abnormal glucose tolerance and coagulopathy; whereas male F1 offspring exhibited abnormal glucose tolerance and increased visceral fat accumulation compared with F1 sex-matched offspring born to saline-treated dams. Both male and female F1 offspring born to LPS-treated dams had evidence of anemia. Fetuses (F2) from F1 females born to LPS-treated dams were growth restricted, and this reduction in fetal growth was associated with increased CD68 positivity and decreased expression of glucose transporter-1 in their utero-placental units. These results indicate that abnormal maternal inflammation can contribute to increased risk of CV and metabolic disease in offspring, and that the effects of inflammation may be transgenerational. This study provides evidence in support of early screening for CV and metabolic disease, as well as pregnancy complications in offspring affected by pre-eclampsia or other pregnancy complications associated with aberrant inflammation.

developmental biology↗