Brianna Francis, a sophomore at Johns Hopkins University majoring in Molecular and Cellular Biology and minoring in Computational Medicine, analyzed IDH1-mutant skin cutaneous melanoma subtypes.
Skin cutaneous melanoma is a form of cancer with a very high mutation burden. Varying combinations of mutated genes can affect tumor development, prognosis, and the efficacy of therapy. I am extremely fortunate to have had the opportunity to participate in a research project at the Broad. It has been a truly life-changing experience where I have faced numerous challenges that have allowed me to grow as a scientist and a person. The Broad Summer Research Program has opened the door to many meaningful connections with not only renowned scientists, but other students who are also passionate about asking questions at the frontiers of knowledge.A common gain-of-function mutation in melanoma is in the IDH1 gene, which has been shown to impact DNA methylation, a gene repression mechanism. Other mutations known to impact melanoma phenotype are in the BRAF or NRAS genes. Previous studies have not explored the potential synergy between these mutations in melanoma. We aim to investigate whether there are significant differences in gene expression and DNA methylation between melanomas with IDH1-NRAS and IDH1-BRAF mutations. Uncovering differences between the two groups would allow us to understand the distinctive consequences of each combination of mutations. We are analyzing skin cutaneous melanoma DNA methylation array and gene expression mRNA-seq data from The Cancer Genome Atlas.
We have found that all tumor samples with IDH1 gain-of-function mutations have relatively high DNA methylation levels and a downregulated set of genes. At a subset of probes, samples with IDH1-NRAS mutations display higher levels of DNA methylation than samples with IDH1-BRAF or IDH1 “only” mutations. We have found that these regions are enriched in Polycomb target genes. Polycomb complexes are known to repress genes important during early development. We investigated if hypermethylation at this subset of probes in IDH1-NRAS (compared to IDH1-BRAF) impacted the expression of the Polycomb target genes close to the probes and we found that there was no clear change in expression. Many highly methylated genes in IDH1-NRAS samples which are enriched in Polycomb are still highly expressed. This discovery suggests a nuanced relationship between DNA methylation and gene expression in melanoma tumor samples. Analyzing the epigenomic and transcriptional differences across tumor samples will allow scientists to develop targeted therapies so that patients with melanoma receive the most effective treatments based on their tumor subtype.
Project: Analyzing subtypes of IDH1-mutant skin cutaneous melanoma
Mentor: Elena Torlai Triglia, Epigenomics Program, Bernstein Lab