Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.

The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.

The Joubert syndrome protein ARL13B binds tubulin to maintain uniform distribution of proteins along the ciliary membrane.

Cilia-mediated signal transduction involves precise targeting and localization of selected molecules along the ciliary membrane. However, the molecular mechanism underlying these events is unclear. The Joubert syndrome protein ARL13B is a membrane-associated G-protein that localizes along the cilium and functions in protein transport and signaling.

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway.

Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis.

Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior.

Based on studies in mice and humans, cohesin loss from chromosomes during the period of protracted meiotic arrest appears to play a major role in chromosome segregation errors during female meiosis. In mice, mutations in meiosis-specific cohesin genes cause meiotic disturbances and infertility. However, the more clinically relevant situation, heterozygosity for mutations in these genes, has not been evaluated.

Oocyte cohesin expression restricted to predictyate stages provides full fertility and prevents aneuploidy.

To ensure correct meiotic chromosome segregation, sister chromatid cohesion (SCC) needs to be maintained from its establishment in prophase I oocytes before birth until continuation of meiosis into metaphase II upon oocyte maturation in the adult. Aging human oocytes suffer a steep increase in chromosome missegregation and aneuploidy, which may be caused by loss of SCC through slow deterioration of cohesin [1-3]. This hypothesis assumes that cohesin expression in embryonic oocytes is sufficient to provide adequate long-term SCC.