DNA mutations in oncogenes and tumor suppressor genes drive tumorigenesis, but epigenetic modifications, such as DNA methylation, take center stage in a new era of cancer research.1 In a study published in Cancer Cell, researchers cast a wide -omics net to capture extensive DNA methylation, transcriptomic, and proteomic data from almost 700 tumors and healthy tissues. 2 Their findings help unravel the complex effects of methylation on tumor development.
“This study really provides the first look at how methylation and epigenetic modification of the DNA eventually have an impact on the protein abundance, and that those proteins are actually driving cancers,” said Li Ding, an expert in cancer genomics at Washington University in St. Louis and author of the paper.
Scientists often use proteomics data in a targeted way in cancer research, for example, to detect biomarkers in blood for specific cancer types.3 Ding and her colleagues wanted to perform a much broader study to identify entirely new factors involved in the onset of cancer. It was no small feat. They simultaneously ran DNA methylation, transcriptomic, and proteomic analyses to investigate more than 10,000 genes and proteins across seven different cancer types. This unbiased approach allowed them to discover previously unknown methylation events that affect protein levels and drive cancer.
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One finding in particular caught Ding’s attention. Hypomethylation on fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase (RTK) oncogene, increased transcript and protein abundance and drove cancer activity. Genetic mutations in FGFR2 drive tumorigenesis, particularly in endometrial cancer, but Ding’s evidence shows that epigenetic modifications similarly promote oncogenesis.
“We’re very excited about this because it’s a breakthrough, and it’s very definitive,” Ding remarked. “We also found that [methylation and genetic mutations] are often mutually exclusive. When you have hypomethylation of FGFR2, you often don’t see the mutations, and vice versa.”
Similarly, the team found that epidermal growth factor receptor (EGFR), another RTK oncogene, is also regulated by both genetic and epigenetic drivers. In fact, hypomethylation of EGFR, which corresponded to an increase in EGFR transcripts and protein abundance, was common across multiple cancer types.
Ding and her colleagues found that epigenetic modifications also affect transcription factors, causing far-reaching effects on the larger gene networks that they control. For example, hypermethylation of signal transducer and activator of transcription 5A (STAT5A) correlated with a reduction in both the RNA transcripts and proteins produced by the genes it regulates. The effects of these epigenetic edits extended to the tumor microenvironment, reducing the number of immune cells available to combat tumor growth.
Stephen Baylin, a cancer biologist at Johns Hopkins Medicine who was not involved in the study, said that he was enthusiastic about the results of the paper and Ding’s approach. “I would add that it's really important to stratify these events, not only to establish cancers but premalignancy and how [the tumors] evolved from the parent cells, and drill down on that even more,” Baylin remarked.
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According to Ding, the results of the study highlight potential druggable targets. Almost 20 percent of the tumors studied could potentially be treated by targeting methylated genes like EGFR. They also postulated that pharmacological activation of hypermethylated STAT5A signaling could boost the antitumor immune response, increasing inflammation to warm up uninflamed tumors.4
“This will have particular interest for clinicians who are actually developing strategies for treating patients by employing or leveraging the immune system within the tumor,” Ding concluded.
- Kay J, et al. Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst). 2019;83:102673.
- Liang W-W, et al. Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin. Cancer Cell. 2023;41(9):1567-1585.e7.
- Miyauchi E, et al. Identification of blood biomarkers in glioblastoma by SWATH mass spectrometry and quantitative targeted absolute proteomics. PLoS One. 2018;13(3):e0193799.
- Bonaventura P, et al. Cold tumors: A therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168.