Epigenetic Changes in Cancer Progression

The path a cell takes from healthy to metastatic cancer is mostly driven by epigenetic changes, according to a new computational study. Dr. Eduard Porta, group leader of the Cancer Immunogenomics group at the Josep Carreras Leukaemia Research Institute, participated in the new analysis that has been recently published in the journal Nature.

Every cell makes its own proteins by accessing the genetic information on its genes. Changes in this information, called mutations, may ruin the function of the affected proteins. In oncology, this is regarded as the genetics of cancer. The last decades, however, have seen the rise of a new field: the epigenetics of cancer.

Epigenetic modifications do not change the information but transiently modifies the cell’s ability to read some of its own genes and produce the associated proteins instead. There is a vast epigenetic programme controlling in such way the general working of the cell and, when altered, it may put it at the starting line of malignant transformation. Is there a way to track these changes and understand the epigenetics of cancer transition?

An international team of researchers has started to unlocked this long-awaited milestone. In a tour de force, they analysed 1.7 million cells from 225 samples from primary and metastatic origin, from 205 patients of 11 different cancer types. For each cell, the team obtained the full transcriptome, exome and epigenome. This covers virtually all gene mutations, gene accessibility and its consequences. Using vast computational power, they could deduce the whole functional status of each analysed cell and link it to its particular cancer type.

The results of the work, published in the scientific journal Nature, demonstrate that many regions in the DNA are differentially activated or inactivated in a cancer-specific manner, creating a signature for each tumour. These differences are relevant for cancer progression and many correspond to already identified hallmarks of cancer, the steps a cell must undergo to become malignant. Dr. Eduard Porta, group leader at the Josep Carreras Leukaemia Research Institute (IJC-CERCA), is part of the team and contributed with his experience in the analysis of large amounts of biological data.

Epigenetic changes at the DNA level stand out as an underlying cause of cancer, according to the new publication. Particularly, the accessibility of enhancer regions, a kind of master regulator acting upon many genes at once. Taken together, the results converges into a short list of genes that can be used as markers for good or poor prognosis, valuable information for the clinical management of patients.

The analysis has also identified the cellular pathways of these important genes, making it possible to track their distant interactions. Sometimes, the affected genes are so fundamental that is impossible to drug them directly without side effects but, knowing the full pathway, researchers may develop strategies to target the weakest link in the chain, maximising the therapeutic benefits while minimising undesirable effects.

Sources:

Nadezhda V. Terekhanova, Alla Karpova, Wen-Wei Liang, Alexander Strzalkowski, Siqi Chen, Yize Li, Austin N. Southard-Smith, Michael D. Iglesia, Michael C. Wendl, Reyka G. Jayasinghe, Jingxian Liu, Yizhe Song, Song Cao, Andrew Houston, Xiuting Liu, Matthew A. Wyczalkowski, Rita Jui-Hsien Lu, Wagma Caravan, Andrew Shinkle, Nataly Naser Al Deen, John M. Herndon, Jacqueline Mudd, Cong Ma, Hirak Sarkar, Kazuhito Sato, Omar M. Ibrahim, Chia-Kuei Mo, Sara E. Chasnoff, Eduard Porta-Pardo, Jason M. Held, Russell Pachynski, Julie K. Schwarz, William E. Gillanders, Albert H. Kim, Ravi Vij, John F. DiPersio, Sidharth V. Puram, Milan G. Chheda, Katherine C. Fuh, David G. DeNardo, Ryan C. Fields, Feng Chen, Benjamin J. Raphael, Li Ding. Epigenetic regulation during cancer transitions across 11 tumour types. Nature, 2023; DOI: 10.1038/s41586-023-06682-5

Josep Carreras Leukaemia Research Institute. (2023, November 6). Epigenetic changes are paramount in cancer progression. ScienceDaily. Retrieved November 7, 2023 from www.sciencedaily.com/releases/2023/11/231106134756.htm

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