Epigenetic drivers of cancer progression
Epigenetic alterations are modifications to the genome that do not involve changes in the DNA sequence but can still alter gene expression and contribute to cancer progression. Epigenetic alterations can be broadly categorized into DNA methylation, histone modifications, and non-coding RNA-mediated mechanisms.
DNA methylation is a modification to the DNA molecule that involves the addition of a methyl group to the cytosine nucleotide in a CpG dinucleotide context. DNA methylation is associated with gene silencing and is frequently altered in cancer. For example, hyper methylation of the promoter region of the tumor suppressor gene CDKN2A is a common event in many cancers and is associated with decreased expression of this gene.
Histone modifications, on the other hand, involve alterations to the proteins around which DNA is wrapped, called histones. These modifications can alter chromatin structure and gene expression. For example, acetylation of histones is associated with gene activation, while methylation of histones can be associated with gene repression. Non-coding RNAs, including microRNAs and long non-coding RNAs, can also contribute to epigenetic alterations in cancer. These RNAs can regulate gene expression by binding to messenger RNA transcripts and inhibiting their translation into proteins or by regulating chromatin structure.
Precision medicine and genetic and epigenetic drivers of cancer
The identification of genetic and epigenetic drivers of cancer has led to the development of precision medicine approaches that aim to personalize cancer treatment based on the specific molecular alterations driving each individual patient's tumor. For example, tumors with mutations in the EGFR gene are sensitive to treatment with EGFR inhibitors, such as erlotinib and gefitinib. Similarly, tumors with mutations in the BRAF gene are sensitive to treatment with BRAF inhibitors, such as vemurafenib and dabrafenib.
Epigenetic alterations in cancer can also be targeted with precision medicine approaches. For example, inhibitors of DNA methyltransferases, such as azacitidine and decitabine, are approved for the treatment of some hematologic malignancies. Similarly, inhibitors of histone deacetylases, such as vorinostat and romidepsin, have been approved for the treatment of cutaneous T-cell lymphoma.