5' UTR mutations in prostate cancer

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Published: 15 Apr 2019
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Dr Yiting Lim, Fred Hutchinson Cancer Research Center, Seattle, USA

Dr Yiting Lim speaks to ecancer at the 2019 American Association for Cancer Research (AACR) meeting about the 5' UTR mutations that are present among the DNA of prostate cancer patients.

Dr Lim emphasises the significance of this research, as mutations in the 5' UTR are often overlooked and require more research. 

By using publically available datasets, localised patient DNA was examined for 5' UTR mutations.
The group also sequenced genomic DNA acquired from patients with metastatic castration-resistant prostate cancer. The somatic mutations identified (mostly SNPs, but some short insertions/deletions) were found to be recurrent within the whole patient cohort.

Dr Lim states that the results of this study suggest the importance of post-transcriptional regulation potential therapies should focus on mechanisms around this. She also mentions the possibility of personalising these treatments to target a patient's specific mutations.


 

I study the 5’ UTR mutations in prostate cancer. The 5’ untranslated regions are part of the non-coding genome which are largely understudied and form a huge portion of our DNA. I studied untranslated regions which are part of this region and found that there are mutations that can alter gene expression in prostate cancer so that forms a repository of resources for finding new therapies for prostate cancer patients.

How did you go about doing this?

We looked firstly at localised patient DNA available in publically available datasets in TCGA and ICGC. So we called up mutations in these regions but we also additionally sequenced metastatic castration resistant prostate cancer genomic DNA from patients enrolled in the University of Washington rapid autopsy programme. So we have about 80 patients and we also call mutations within the 5’ untranslated regions of these patients. We compared these somatic mutations and found that they are recurrent within our entire patient cohort and we analysed what these mutations did to change transcription and translation.

What types of mutations did you find?

Most of these mutations are single nucleotide variants; a small number are short insertions and deletions.

Could there also be a vulnerability to epigenetic changes that might result in prostate cancer?

This region could be vulnerable to epigenetic changes but our dataset did not include this. So that could be something that we can look further into.

How did the systemic mutations corroborate with patient outcomes?

We found a group of them in metastatic prostate cancer tissues that were mutated within the MAPK signalling pathway. When we looked at the patient characteristics of this subset of patients they do present with more bone metastases at diagnosis, suggesting that there might be some clinical relevance there.

How could these results translate into potential future therapies?

The outcome of this study suggests that post-transcriptional regulation is super-important in prostate cancer. So hopefully down the line we can focus the biology on post-transcription mechanisms and have this new area be a source for down the line potential therapies.

How could we personalise these therapies in the future?

To personalise these therapies we can potentially look for mutations within the untranslated regions in prostate cancer to stratify how they can be targeted for therapy.

What do you expect to see from this research in the near future?

Over the next few years I would hope that there will be more interest in the post-transcriptional mechanisms of gene expression in cancer, especially in prostate cancer and to further study the mechanistic functions of what these mutations can potentially do to alter transcription and translation.