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Science Papers on Cancer Mutational Signatures, System to Deliver CRISRP-Cas9 Machinery Across Blood-Brain Barrier

By sequencing tumors from thousands of cancer patients and comparing them to similar datasets generated by other research groups, a team led by scientists from the University of Cambridge has identified new mutational signatures of cancer, while also uncovering details about organ-specific common and rare signatures. In the study, which appears in this week's Science, the investigators performed mutational signature analyses on 12,222 whole genome-sequenced tumor/normal matched pairs from patients recruited via the UK National Health Service. They then contrasted their findings with two independent cancer whole-genome sequencing datasets — one from the International Cancer Genome Consortium and the other from the Hartwig Medical Foundation — involving a total of 18,640 whole genome-sequenced cancers. They uncovered 40 single-base substitution mutational signatures and 18 double-base substitution mutational signatures that have not previously been reported. They also show that cancers have a limited number of common signatures and a long tail of rare signatures for each organ. Notably, the researchers find that most of the common signatures have already been identified and that many of the previously unreported signatures are low-frequency, rare processes, indicating that "the landscape of signatures is thus likely to be saturating." GenomeWeb has more on this, here.

A novel system for delivering CRISRP-Cas9 anticancer payloads across the blood-brain barrier (BBB) is described in Science Advances this week. Currently, most CRISPR-Cas9 delivery approaches targeting the brain rely on viral vectors, which have a number of limitations including low packing capacity and the potential to induce undesirable genetic mutations. To address this, scientists from Henan University developed a nanocapsule composed of a glutathione-sensitive polymer shell decorated with a ligand that binds to receptors highly expressed on both BBB endothelial cells and glioblastoma cells and that facilitates Cas9/small guide RNA release. Using the nanocapsule, the researchers were able to deliver Cas9/sgRNA complexes targeting Polo-like kinase 1, which plays a role in cell mitosis and is a key glioblastoma target, into mouse models with minimal off-target effects. Importantly, the treatment significantly extended the animals' median survival time.

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