The frontier of RNA science is very nonmessenger. A decade ago, the noncoding RNA field was likened to dumpster diving.
Obscured in the bottom corner of the dumpster were what have come to be known as orphan noncoding RNA, or oncRNA. It’s still unclear the purpose of this new type of genetic material, which was discovered and named in Palo Alto-based researcher Hani Goodarzi’s lab in 2018.
Now, his team’s latest findings push further forward the notion that oncRNA-based liquid biopsies may someday play a pivotal — and, excitingly, multipurpose — role in precision oncology and beyond.
Presented in Cell Reports Medicine, Goodarzi’s team showed there are 260,968 different oncRNA that combine with predictable patterns likened to digital barcodes so specific that they suggest entirely new tumor subtypes across a range of cancers whose cells secrete oncRNA into the blood. A proof-of-concept phase of the research linked oncRNA with breast cancer metastasis.
The extensive nature of the paper and its pan-cancer analyses are buzzworthy, onlookers say.
“It’s not just a risk classifier. It’s not just a diagnostic molecule. It’s not just a tool that will help us subtype tumors. It really is hitting on a lot of different areas, and I think that’s what might be garnering the buzz around these orphan noncoding RNAs,” said Yitz Goldstein, MD, section chief of molecular diagnostics in the Montefiore Medical Center in Bronx, New York. He wasn’t involved in the study.
Goodarzi admitted every bit of his team’s years of work was piled into the single paper because most have left to join the startup company he co-founded, Exai Bio, and “the overhead of multiple papers wasn’t an option.”
The RNA Bet
Why Goodarzi is even in the middle of the wild west of RNA is serendipitous, he acknowledged. He started his lab in 2016 and wanted to investigate whether cancer cells can engineer their own pathways of gene expression control.
“To be honest, we didn’t really set out to solve a molecular diagnostic problem. It was actually one of these high-risk, high-reward kind of bets,” said Goodarzi, a PhD multidisciplinary scientist with expertise in AI and machine learning and in cancer systems and RNA biology. He is a co-investigator at ARC Institute and an associate professor of biochemistry and biophysics at the University of California San Francisco (UCSF).
Goodarzi described his initial research question as: Is cancer really a dysregulation of normal cells — an evolutionary disease — or do cancer cells go “beyond what is available to them in normal cells, and instead do just entirely new things — new molecular mechanisms?”
The 2018 identification of oncRNA garnered a lot of skepticism for its translational potential. Stanford professor of medicine and liquid biopsy researcher Ash Alizadeh, MD, PhD, knows how arduous the translational path is — his lab’s work has led to new technologies that made it to market. He’s followed Goodarzi’s work and said his skepticism of oncRNA persists but is much lower after the latest paper.
“I am a little bit more convinced than I was a decade ago that these things can be functional,” said Alizadeh, noting two main aspects driving oncRNA’s clinical prospects. “The number of these oncRNAs across cancer, at a quarter million, seems like a lot. That’s a big number to have your pick from. The second is the diversity and the pattern of their variation across cancers in a way that can serve as a barcode of the identity of a lineage — a fingerprint of the tumor type as molecules that you can count digitally and do cool things with. Those are the big surprises for me that I think are likely to be important.”
The ‘Aha Moment’
The foundational oncRNA work was primarily done in breast cancer because of Goodarzi’s relationship with the I-SPY breast cancer researchers at UCSF who are attempting to personalize breast cancer treatment by finding which cancer types respond to which treatments. So when it came time to expand their understanding of oncRNA, the team at first considered looking at colon cancer because they also work in that space.
“Then we thought, maybe we’ll just do it across the board,” Goodarzi recalled, and applied their efforts to the entire dataset from the Cancer Genome Atlas.
First author and bioinformatician research assistant Jeff Wang created a binary map of oncRNAs that quickly demonstrated two important things. First, there are tens of thousands of them. And second, it was visually apparent there are cancer-specific patterns.
“That was another kind of ‘aha’ moment that you showed that you can actually train good classifiers simply based on which oncRNAs are present in a sample, not even at the expression level, but just presence or absence, and tell which tumor it comes from,” Goodarzi said.
At that moment, he paused and asked “what it really meant to have these cancer-emergent RNAs? So where do they actually come from?”
So they traced them.
About 60% come from longer RNA, while the remaining 40% trace back to cancer tissue but not surrounding healthy tissue, suggesting that — as they explained in the paper — “oncRNA biogenesis may arise from cancer-emergent transcription events in regions with increased chromatin accessibility.”
“They come from the same regulatory processes now rewired and broken in the context of cancer, but they are part of the gene regulatory network of the cell,” Goodarzi said. “And we showed, for example, a large part of them very clearly come from dysregulations in the epigenome. So parts of the chromatin that is usually closed opens up and you get new transcriptional events in these regions and you get these now fragments of RNA that we have defined as oncRNAs. We are capturing this gene regulatory network of the cell.”
This is not, however, what’s known in the traditional sense of reprogramming of the cancer genome during disease, which “usually manifests itself as gene expression changes, which we have loved and studied to death for like three decades and everywhere,” Goodarzi said.
“Now it turns out that there’s this flip side of the coin, where these regulations are giving rise to these new RNAs that are, instead of going up and down, they’re appearing as a zero-one digital signal,” he said.
Still…What Do oncRNA Do?
The majority of what we know about cancer biology is based on the understanding that proteins execute functions. Still, no one knows what oncRNA do.
Bypassing the existential question is part of what propelled the discovery.
Long noncoding RNA researcher Nadya Dimitrova, PhD, called the Goodarzi team’s work “really creative” because at the time most other scientists were studying RNA with known functions.
“Everybody else was looking at the big shiny thing, and they discovered an even bigger trove of data that everybody was just glossing over and ignoring,” said Dimitrova, associate professor in the Department of Molecular, Cellular, and Developmental Biology at Yale School of Medicine, New Haven, Connecticut.
To learn that oncRNA can be cancer-specific, defining tissue of origin and differentiating between cancer subtypes “are very important findings,” she said, although not entirely surprising because other noncoding RNA work has come to similar conclusions and yet “physicians, physician scientists, and most biologists have ignored noncoding RNAs.”
The Goodarzi work reinforces “that these noncoding RNAs, even if we don’t know where they come from, even if we don’t know what they do, we know that they’re actually a more accurate representation of the cancer,” Dimitrova said.
In this protein-centric world, the pressure is on to perform good science and drive the field of noncoding RNA forward now that the potential has been well-defined, she added.
Clinical labs are ready and waiting. Goldstein said he’s keeping tabs on scientific papers like this because he knows breakthroughs are imminent based on recent hematologic advances. The currently used biomarker panel at Montfiore can guide therapies in less than a day for many cancers, and a recently adopted panel for suspected acute leukemia can guide targeted therapy in two days’ time, compared to 7 to 10 days for results at other labs. The solid tumor panel has remained unchanged, though, for several years.
“What this paper really highlights is that the more we learn, the more we realize the less we know. And that there’s an ever-growing ‘-ome,’” Goldstein said. “There’s the proteome. There’s the methylome. There’s now an RNA-ome — a transcriptome. And so there’s a never-ending -ome of learning here, of new molecules. Many of those will not make their way to the bedside, but the ones that do are already having an impact in patient care. And we can really be excited about what’s to come.”
Alizadeh disclosed that he is the co-founder of the company Resero Bio. Goodarzi disclosed that he is a co-founder and board of directors member of Exai Bio. Disclosure information for study authors is available in the original study publication.
https://www.medscape.com/viewarticle/bar-code-biopsy-rna-could-guide-precision-oncology-2026a1000coj
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