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Nature Papers on Alzheimer's Disease Development, Whole-Genome Doubling in Cancer, More

Combining genetic and proteomic data from Alzheimer's disease patients, a team led by researchers from Emory University has uncovered new details about how the degenerative brain condition develops. As reported in Nature Genetics, the scientists integrated Alzheimer's disease genome-wide association study results with human brain proteomes to identify genes that confer disease risk via their effects on brain protein abundance. They identified 11 genes that appear causal in Alzheimer's disease, including eight that represent novel risk genes, and which may be targets for further mechanistic and therapeutic studies.

Whole-genome doubling (WGD), a common occurrence in cancers, creates genetic vulnerabilities in tumor cells that could be therapeutically targeted, according to a new study in this week's Nature. WGD events occur early in tumorigenesis and generate genetically unstable tetraploid cells that drive tumor development. Using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from around 600 cancer cell lines, investigators from Boston University show that WGD not only results in common genetic traits that favor tumorigenesis but imposes adaptive requirements on cells that could potentially be exploited. For instance, the team identified a gene called KIF18A that encodes a mitotic kinesin protein and is specifically required for the viability of WGD cells.

Using single-cell RNA sequencing (scRNA-seq), spatial profiling of human tumors, and genetic and pharmacological perturbations in cellular models, a research group led by investigators from the Broad Institute gained insights into the relationship between the immune and genetic mechanisms in the soft tissue cancer synovial sarcoma (SyS). In their study, which appears in Nature Medicine, the researchers performed scRNA-seq profiling on 16,872 cells from 12 human SyS tumors along with spatial transcriptomic and multiplex immunofluorescence of tumors. They find a malignant cellular state in all SyS tumors that is predictive of poor prognosis and immune evasion. This state, they write, is driven by the SS18-SSX fusion oncoprotein that underlies SyS, is repressed by immune cells, and can be targeted with a combination of anticancer HDAC and CDK4/CDK6 inhibitors. "Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies," the study's authors write.