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Genome Biology Papers on Pediatric Bone Accrual, Pancreatic Cancer Metastases, Urothelial Carcinoma

A Children's Hospital of Philadelphia-led team identifies dozens of genetic loci linked to longitudinal pediatric bone accrual using genome-wide association study, variant-to-gene mapping, and functional approaches. With some 11,000 bone scans done on healthy children and adolescents over time, the researchers considered bone accrual in relation to individuals' genotypes. The search led to 40 bone accrual-related loci, including variants in or around bone-related genes and genes implicated in later adult fracture risk. They further explored such findings with ATAC-seq-based chromatin mapping, promoter interaction capture assays, gene knockdown experiments, and CRISPR-Cas9-based gene editing. "Our findings implicate multiple biological pathways involved in variation in bone accrual, and highlight the switch between osteogenesis and adipogenesis as potentially critical in pediatric bone accrual," the authors write, adding that "in-depth longitudinal phenotyping plus appropriate function follow-up of GWAS loci can yield greater insight into dynamic, complex traits such as bone accrual."

Researchers from the Shanghai Jiao Tong University, the Chinese Academy of Sciences, and elsewhere describe a role for the immune-related complement cascade gene C1q in pancreatic ductal adenocarcinoma (PDAC) metastases in the liver. Based on exome and RNA sequence profiles on matched normal pancreatic, primary tumor, and liver metastasis tumor samples from 17 individuals with hepatic oligometastatic forms of PDAC, the team identified recurrent chromosome 3 losses, enhanced proliferation, and other features that appeared to be distinct to the liver metastases — results they confirmed with samples from nearly three dozen more cases. In the microenvironment surrounding the hepatic metastases, meanwhile, the authors documented an uptick in complement cascade activity and higher-than-usual representation by tumor-infiltrating M2 macrophages that appeared to produce migration- and invasion-promoting complement C1q in both the primary and metastatic settings.

Finally, investigators in the US, China, and France provide details from a genetic, epigenetic, and immune analysis of upper tract urothelial carcinomas (UTUC), comparing features in 20 muscle-invasive and 20 non-muscle-invasive versions of the disease. Among other recurrent mutations and, the team's exome sequencing, targeted sequencing, RNA sequencing, array-based methylation, and clinical data highlighted two groups of tumors with distinct epigenetic features: a set of immune-depleted tumors with lower-than-usual methylation and frequent FGFR3 mutations that were enriched in non-muscle-invasive cases, and a group of more immune-infiltrated, hypermethylated tumors that were frequently marked by mutations in the SWI/SNF genes and tended to be muscle-invasive. "These data pave the way for therapeutic interventions in the most threatening subgroup of UTUC," the authors write, "providing a rationale for personalizing therapies in this setting."