Person:

Wala, Jeremiah

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Recent studies have detailed the genomic landscape of primary endometrial cancers, but their evolution into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors, and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

Far from a random tangle, cellular DNA is packed into the nucleus with astounding precision. Indeed, there is growing appreciation for how the three-dimensional (3D) organization of the genome contributes to controlling gene expression. For instance, loops of DNA called insulated neighborhoods can protect small groups of genes from silencing or activation (1). If cancer can result from dysregulation of gene expression (2), then an enticing hypothesis is that disrupting insulated neighborhoods may lead to increased transcription of cancer genes. On page 1454 of this issue, Hnisz et al. (3) use tumor-derived sequencing data and targeted deletions in cells to show that disruption of insulated neighborhoods leads to activation of proto-oncogenes—genes with the potential to cause cancer. These findings strongly support disruption of chromatin structure as causally linked to tumorigenesis, and suggest that such disruptions may be the hidden culprit driving many tumors.