Highlights in Cancer Research: January 2023

“It’s an amazing story how one nucleotide change in the non-coding genome can dramatically alter cancer susceptibility in large number of patients. ” EACR Board

Genome-wide association studies have found multiple single-nucleotide polymorphisms (SNP) that are associated with glioma, but the mechanism of action for nearly all the polymorphisms has long been unknown. Prior studies had found the SNP rs55705857 was associated with risk of developing IDH-mutant gliomas; this SNP was located in a region of the genome that has been of interest in many different cancer types. Fine-mapping of the locus narrowed the region of interest and again confirmed that the rs55705857-G risk allele is the likely causative allele. Histone chromatin immunoprecipitation showed that the rs55705857 locus encompasses a brain -specific enhancer and demonstrated increased enhancer activity in human IDH-mutant versus IDH-wildtype glioma. Reporter assays in mouse embryos further observed increased activity of the enhancer containing the rs55705857-G risk allele.

To functionally test the rs55705857 alleles in the generation of tumors, a mouse model of IDH-mutant low-grade glioma was developed. Mice with a rs55705857-G knock-in allele developed IDH-mutant gliomas with significantly decreased latency and increased penetrance compared to mice carrying the wildtype rs55705857-A non-risk allele. ChIP-PCR in mouse IDH-mutant tumor cell lines found that OCT2, OCT4 and SOX2 bound preferentially to the rs55705857-A non-risk allele. Primary mouse neural and oligodendrocyte progenitor cells carrying the risk allele exhibited upregulated MYC mRNA and protein expression compared to cells from non-risk littermates. This suggests that rs55705857-G is increasing MYC expression by disruption of OCT2/4 repression by a long-range DNA-DNA interaction at the MYC locus.