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PNAS Study of Thyroid Cancer Polygenic Risk Scores; LOF Mutation in Cerebellar Degeneration; More

An international team of researchers examined how well polygenic risk scores for papillary thyroid cancer predicted risk among three cohorts: one from Ohio, one from the UK, and one from Iceland. Previous genome-wide association studies had identified about 10 SNPs linked to papillary thyroid cancer risk, which the researchers bundled into a PRS. As they report in the Proceedings of the National Academy of Sciences this week, the researchers found that this PRS performed equally well in those three populations. An extended PRS score based on more than 590,000 common variants did not have significantly improved predictive power over that of the much smaller 10-SNP score. Individuals in the top decile group, as gauged by the 10-SNP score, had about a sevenfold increased risk of papillary thyroid cancer. "Our work demonstrates that the 10 low-penetrance variants have the potential to be applied in medicine to improve individualized cancer risk assessment," the researchers note in their paper.

Researchers uncovered a loss-of-function mutation affecting a voltage-gated sodium (BK) channel in a 16-year-old patient with progressive cerebellar degeneration. Researchers from the University of Chicago sequenced her exome to uncover a de novo mutation in the KCNMA1 gene that affects the selectivity filter of the channel. BK channels with this alteration are trafficked to plasma membranes as expected, but the alteration affects neurite outgrowth, cell viability, and mitochondrial content and, in mice, leads to gait impairment. Treatment with the BK/SK channel activator chlorzoxazone partially improved motor function in the patient, they report. These findings "indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability," the authors write.

To study the effect of arachidonic acid epoxides on tumor growth, researchers from Goethe University in Germany crossed mice lacking Cyp2c44, a cytochrome P450 enzyme that is involved in generating arachidonic acid epoxides, into a mouse model of breast cancer. The resulting mice had increased tumor growth and metastasis, and the tumors that arose in these mice had more tumor-associated macrophages, high lymphangiogenesis, and higher prostaglandin levels than did mice with Cyp2c44. The researchers note that the boost in prostaglandin levels could be because Cyp2c44 would normally metabolize the prostaglandin precursor. A proteomic analysis further found tumors within these mice upregulate the WD repeating domain FYVE, which is involved in the inflammatory Toll-like receptor signaling pathway.