Renal Cancer: A Paradigm for Understanding How Mutations in Epigenetic Regulator Genes Drive Cancer Initiation and Progression
It is now well established that genes regulating epigenetic marks are mutated at high frequency in a broad spectrum of human cancers. For example, the ten-eleven translocation (TET) family of proteins is mutated in nearly 30% of myeloid malignancies overall, and in up to 60% in certain subtypes such as chronic myelomonocytic leukemia (CMML). The mechanisms by which these mutations initiate and promote cancer and metastasis is likely distinct from that of traditional tumor suppressor genes such as p53, demanding a better mechanistic understanding of how they regulate cell growth and differentiation. Elucidating their mechanism of action is also expected to yield novel therapeutic vulnerabilities created by these mutations that can be developed into new targeted therapies.
To study this process, model cell culture and animal systems are being developed to probe the impact of several commonly occurring epigenetic regulator gene mutations on the epigenome and transcriptome levels, at single genes and over the entire genome. At present, these genes include TET2, DNMT3A, SETD2 and the NSD family. Renal cell cancer, one of the focus areas of the Epigenetic Etiology of Human Disease Laboratory, is distinctive because it is heavily dominated by epigenetic regulator gene mutations (including SETD2, PBRM1 and BAP1) while presenting with relatively low mutation frequency of traditional tumor suppressor genes such as p53. SETD2 is a histone methylase that trimethylates the histone H3 lysine 36 (H3K36) position, a mark enriched in the bodies of actively transcribed genes. Interestingly, H3K36me3 recruits DNMT3A and DNMT3B to promote DNA methylation within gene bodies and in some regions of the genome antagonizes the function of the repressive PRC2 complex.
Our laboratory showed that mutations in SETD2 globally deregulate DNA methylation patterns and create a DNA hypermethylator phenotype that may promote more-aggressive forms of clear cell renal cell carcinoma (ccRCC). By understanding the mechanisms underpinning epigenetic regulator mutations such as SETD2, we can better understand how they drive tumor initiation and progression, and impact patient survival and response to treatment.
These studies are also expected to yield novel and personalized treatments for people with cancer presenting with mutations in epigenetic regulator genes. The research team hypothesizes that tumors with epigenetic mutations will be more susceptible to drugs that target the epigenome, creating new avenues for individualized therapy.