The use of CRISPR-Cas9 (CRISPR) exhibits gene fusions that are integral in the growth of cancer cells, according to researchers who published their findings in Nature Communications.
Although many gene fusions are reported in tumors, their role remains unknown. The researchers said that “as fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer.”
Researchers developed a multi-algorithm fusion calling pipeline, and integrated large-scale screening data (including CRISPR) to systemically discern functional gene fusions across tissue history and used this pipeline to test 3,354 fusion events. To evaluate the role of fusions in tumor cell activity, they used RNA-sequencing data from 1,011 cancer cell lines to functionally link 8,354 fusion events with genomic data from 43 different cancers, including both pediatric and rare cancers. They assessed the cell lines against more than 350 anti-cancer drugs to observe which existing drugs could be used to treat cancer patients with gene fusions. They then implemented CRISPR as a tool for uncovering which gene functions are crucial for the survival of cancer cells.
Only a Few Gene Fusions “Are Key for Cancer Survival”
According to the results, researchers found that 90% of gene fusions are insignificant in the development of cancer. “We discovered a handful of gene fusions that are key for cancer survival. These genetic changes may present opportunities for treating patients with existing drugs or could be the drug targets of the future,” said Mathew Garnett, PhD, lead author of the study from the Wellcome Sanger-Institute and Open Targets, in a press release. Moreover, the results indicate positive news for patients with rare forms of pancreatic, breast, and lung cancers, as gene fusions involving RAF1, ROS1, and BRD4 were shown to be targetable for existing drugs. Furthermore, the research team uncovered a gene fusion, YAP1-MAML2, which, according to Dr. Garnett “offers a new drug target for several cancers, including ovarian cancer.”
CRISPR catches out critical #cancer changes @NatureComms https://t.co/syIUpyEAXb
— Medical Xpress (@medical_xpress) May 16, 2019
“Cancers differ between people and having a genomic view of these differences is increasing our understanding of cancer and opening up treatment options for patients,” said Dr. Julio Saez-Rodriguez, PhD, previously from European Bioinformatics Institute and Open Targets and now based at Heidelberg University. “This study offers further opportunities to employ gene fusions as therapeutic biomarkers and stratify patients onto clinical trials, potentially offering more targeted and effective clinical studies.”
Overall, the researchers said that their observations support “the use of systematic functional studies in preclinical models as an unbiased platform to systematically assess the impact of fusions in cancer. Extending this approach to a larger set of cancer models that represents the histopathologic and genomic diversity of patient tumors could reveal additional new insights with clinical relevance.”
CRISPR catches out critical cancer changes: New drug target for multiple cancers https://t.co/hPh4krUYgh
— Larry K Chapman (@LKChapman147) May 16, 2019
Source: Nature Communications, EurekAlert