An 'evolutionary relic' of the genome causes cancer

Scientists in the BIDMC Cancer Research Institute discover that the non-coding BRAF pseudogene leads to the development of an aggressive lymphoma-like cancer in animal models

BOSTON -- Pseudogenes, a sub-class of long non-coding RNA (lncRNA) that developed from the genome's 20,000 protein-coding genes but lost the ability to produce proteins, have long been considered nothing more than genomic "junk." Yet the retention of these 20,000 mysterious remnants during evolution has suggested that they may in fact possess biological functions and contribute to the development of disease.

Now, a team led by investigators in the Cancer Research Institute at Beth Israel Deaconess Medical Center (BIDMC) has provided some of the first evidence that one of these non-coding "evolutionary relics" actually has a role in causing cancer.

In a new study in the journal Cell, publishing online today, the scientists report that independent of any other mutations, abnormal amounts of the BRAF pseudogene led to the development of an aggressive lymphoma-like disease in a mouse model, a discovery that suggests that pseudogenes may play a primary role in a variety of diseases. Importantly, the new discovery also suggests that with the addition of this vast "dark matter" the functional genome could be tremendously larger than previously thought - triple or quadruple its current known size.

"Our mouse model of the BRAF pseudogene developed cancer as rapidly and aggressively as it would if you were to express the protein-coding BRAF oncogene," explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and co-founder of the Institute for RNA Medicine (iRM) at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. "It's remarkable that this very aggressive phenotype, resembling human diffuse large B-cell lymphoma, was driven by a piece of so-called 'junk RNA.' As attention turns to precision medicine and the tremendous promise of targeted cancer therapies, all of this vast non-coding material needs to be taken into account. In the past, we have found non-coding RNA to be overexpressed, or misexpressed, but because no one knew what to do with this information it was swept under the carpet. Now we can see that it plays a vital role. We have to study this material, we have to sequence it and we have to take advantage of the tremendous opportunity that it offers for cancer therapy."

The new discovery hinges on the concept of competing endogenous RNAs (ceRNA), a functional capability for pseudogenes first described by Pandolfi almost five years ago when his laboratory discovered that pseudogenes and other noncoding RNAs could act as "decoys" to divert and sequester tiny pieces of RNA known as microRNAs away from their protein-coding counterparts to regulate gene expression.

"Our discovery of these 'decoys' revealed a novel new role for messenger RNA, demonstrating that beyond serving as a genetic intermediary in the protein-making process, messenger RNAs could actually regulate expression of one another through this sophisticated new ceRNA 'language,'" says Pandolfi. The team demonstrated in cell culture experiments that when microRNAs were hindered in fulfilling their regulatory function by these microRNA decoys there could be severe consequences, including making cancer cells more aggressive.

In this new paper, the authors wanted to determine if this same ceRNA "cross talk" took place in a living organism -- and if it would result in similar consequences.

"We conducted a proof-of-principle experiment using the BRAF pseudogene," explains first author Florian Karreth, PhD, who conducted this work as a postdoctoral fellow in the Pandolfi laboratory. "We investigated whether this pseudogene exerts critical functions in the context of a whole organism and whether its disruption contributes to the development of disease." The investigators focused on the BRAF pseudogene because of its potential ability to regulate the levels of the BRAF protein, a well-known proto-oncogene linked to numerous types of cancer. In addition, says Karreth, the BRAF pseudogene is known to exist in both humans and mice.

The investigators began by testing the BRAF pseudogene in tissue culture. Their findings demonstrated that when overexpressed, the pseudogene did indeed operate as a microRNA decoy that increased the amounts of the BRAF protein. This, in turn, stimulated the MAP-kinase signaling cascade, a pathway through which the BRAF protein controls cell proliferation, differentiation and survival and which is commonly found to be hyperactive in cancer.

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An 'evolutionary relic' of the genome causes cancer