Common cancer gene regulates RNA ‘dark matter’


A key genetic mutation that occurs early in cancer alters RNA ‘dark matter’ and causes the release of previously unknown RNA biomarkers for early cancer detection, a new study by researchers from the UC Santa Cruz published in the journal Cell reports shows.

The researchers looked at the effects of mutations in the KRAS gene, which is among the most frequently mutated genes in all cancers, including pancreatic, lung and colorectal cancers. KRAS is thought to be an initial “driver” mutation that leads to the formation of cancer, making it essential for understanding and detecting cancer in its early stages.

In this study, Assistant Professor of Biomolecular Engineering Daniel Kim’s lab focused on KRAS mutations in lung cancer to determine their effects on RNA “dark matter,” which is generated from 75 % of the 3 billion base pairs of the human genome, with the aim of discovering new RNA biomarkers for the early detection of cancer.

“The earlier you detect that a person has cancer, the more likely they are to survive with treatment and surgery,” Kim, who is affiliated with the Institute of Genomics at UC Santa Cruz, told the Institute of Stem Cell Biology, at the Center for Molecular Biology of RNA and an associate member of Stanford’s Canary Center for the early detection of cancer. “Millions of people die of cancer each year worldwide, and there is an urgent need to develop highly sensitive and specific diagnostic tests that allow early detection of cancer, before it spreads to other parts of the body. .”

Kim’s lab studies how the KRAS gene regulates the transcriptome, all the RNA produced in a cell. The most commonly recognized function of RNA is that of a “messenger” that takes the genetic information encoded in DNA and converts it into protein, but recent advances in genomics have revealed that the vast majority of RNA is non-coding and does not make protein. Kim’s lab is focused on finding this non-coding RNA, with the goal of using this information to better understand cancer formation and identify new biomarkers for early cancer detection.

In this study, led by Kim Lab Ph.D. Biomolecular Engineering Candidate and National Institutes of Health F99/K00 Roman Reggiardo Fellow, researchers found that KRAS mutations in lung cancers also activate genes that are stimulated by interferon, which is seen in many cancers but the cause is unclear.

They also determined that KRAS mutations cause a class of genes called KRAB zinc finger genes to be silenced, which Kim says has never been seen before in the context of cancer. When these genes are turned off, certain types of non-coding RNA are aberrantly activated. Many of these newly activated non-coding RNAs are derived from transposable elements, which are repeating elements found in the millions in the human genome, some of which have the potential to “jump” around the genome and modify it.

The researchers found that not only are these transposable element RNAs activated in mutant KRAS cells, but they are also transported outside the cells. Since RNAs are known to be released from cancer cells into the bloodstream, these transposable element RNAs may act as a carcinogenic mutant KRAS signal that can be detected in blood by RNA sequencing.

Kim thinks this strong and robust RNA signature holds great promise for diagnosing cancer in its early stages. This could be done with a blood test known as a ‘liquid biopsy’, a minimally invasive approach compared to a traditional tumor tissue biopsy.

These newly published findings were found through the use of cell culture models, where researchers introduced mutant KRAS into non-cancerous lung cells, pushing them into a cancerous state. They performed RNA sequencing using several different techniques and performed computational analysis to determine which RNA was more prevalent in cells expressing mutant KRAS compared to control cells.

The researchers performed additional epigenomic profiling experiments, which look at how genes are turned on or off without changing the DNA sequence itself. They also performed extracellular vesicle isolations, identifying which RNAs are packaged in extracellular vesicles and preferentially secreted by cancer cells affected by mutant KRAS.

Other labs that contributed to this study include the lab of Associate Professor of Biomolecular Engineering Angela Brooks, the lab of Stanford Radiology Professor Utkan Demirci, the lab of UCSF Medicine Professor Eric Collisson, and Jason Fernandes of laboratory of biomolecular engineering professor David Haussler.

“We were in an interdisciplinary environment that really encouraged us to think about RNA and cancer in a different way,” said first author Reggiardo.

In ongoing and future work, the Kim lab aims to further confirm its new findings by analyzing blood samples from lung cancer patients to validate that their newly identified RNA signatures are present in these patients. This will be done in collaboration with their Stanford Canary Center colleague, Utkan Demirci, and others at Stanford through a collaborative grant from the Department of Defense. They hope to develop a test that could detect these RNA signatures as biomarkers for the early diagnosis of lung cancer.

Moreover, they anticipate that the methods developed in this study could be used as a framework to develop an RNA liquid biopsy platform for the early detection of several cancers.

“Now that we know the RNA signatures of this very early cancer event, it will help us develop new methods for early cancer detection, which will hopefully help save the lives of many people in the future,” said Kim.

Reference: Reggiardo RE, Maroli SV, Halasz H, et al. Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc finger genes. Cell representative. 2022;40(3). do I: 10.1016/j.celrep.2022.111104

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