17 October 2019

Three different studies have highlighted how mutations which disrupt RNA splicing may drive the formation of some cancers, including leukaemias.

The scientists behind the research, all published in last week in Nature, say the findings could provide hope for patients whose cancers are difficult to treat and have high mortality rates.

RNA splicing is the process by which RNA molecules, produced when the DNA code is read by a cell, are cut up and joined in new combinations, forming the blueprints to make proteins. It is essential for producing the diversity of different molecules needed for normal cell functions. However, faulty RNA splicing can lead to absent or non-functioning proteins, or the creation of new proteins with unintended consequences.

Two of the studies, by an Ontario-led research group, reveal the discovery of a novel cancer-driving mutation in non-coding regions of human DNA, sometimes referred to as its “dark matter”.

Dr Lincoln Stein, co-lead of the studies from the Ontario Institute for Cancer Research (OICR), Canada, said the discovery of the mutation could lead to a new potential therapeutic target for several types of cancer including brain, liver and blood cancer. They could also be used to develop novel treatments for patients with these difficult-to-treat diseases.

The U1-snRNA mutation was found in tumours from patients with certain subtypes of brain cancer, including nearly all of the studied samples from adult patients with sonic hedgehog medulloblastoma. It was also found in samples of chronic lymphocytic leukaemia and hepatocellular carcinoma.

“Non-coding DNA, which makes up 98% of the genome, is notoriously difficult to study and is often overlooked since it does not code for proteins,” said Dr Stein.

“By carefully analysing these regions, we have discovered a change in one letter of the DNA code that can drive multiple types of cancer. In turn, we've found a new cancer mechanism that we can target to tackle the disease.”

The research group discovered that the U1-snRNA mutation could disrupt normal RNA splicing, altering the transcription of cancer-driving genes.

Study co-lead Dr Michael Taylor, senior scientist in developmental and stem cell biology, said finding the “typo” in the DNA means the resultant cancers have hundreds of mutant proteins that could be targeted using currently available immunotherapies.

Also published in Nature is a new study which has determined how a single mutation in splicing factor 3b subunit 1 (SF3B1) drives the formation of many cancers.

The study was jointly led by Dr Robert Bradley from Fred Hutchinson Cancer Research Center in Seattle and Dr Omar Abdel-Wahab from Memorial Sloan Kettering Cancer Center in New York.

Because SF3B1 encodes a protein that is critical for producing RNA molecules, they studied RNA sequencing data from hundreds of patients with several different cancer types to search for abnormal RNA molecules.

They found the mutation causes cancer cells to produce an abnormal form of the BRD9 RNA molecule that included non-coding DNA sequences.

Drs Bradley and Abdel-Wahab showed that BRD9 is an important tumour suppressor in many types of cancer, including uveal melanoma, chronic lymphocytic leukaemia and pancreatic cancer. They then designed therapeutics using CRISPR technology and antisense oligonucleotides to reverse the disease process.

While the research is preclinical, the researchers say there is potential to help cancer patients with the SF3B1 mutation via targeted therapeutics.



Suzuki, H., Kumar, S.A., Shuai, S., Diaz-Navarro, A., Gutierrez-Fernandez, A., De Antonellis, P. et al. (2019) “Highly recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma”, Nature, doi: 10.1038/s41586-019-1650-0

Shuai, S., Suzuki, H., Diaz-Navarro, A., Nadeu, F., Kumar, S.A., Gutierrez-Fernandez, A. et al. (2019) “The U1 Spliceosomal RNA is Recurrently Mutated in Multiple Cancers”, Nature, doi: 10.1038/s41586-019-1651-z

Inoue, D., Chew, G.L., Liu, B., Michel, B.C., Pangallo, J., D'Avino, A.R. et al. (2019) “Spliceosomal disruption of the non-canonical BAF complex in cancer”, Nature, doi: 10.1038/s41586-019-1646-9


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