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Every spring, researchers, oncologists, policymakers, journalists, advocacy groups, and patients from around the globe gather at AACR, a scientific conference hosted by the American Association for Cancer Research and the largest of its kind. Matching this spectrum of attendees, the conference’s programming covers a wide array of cancer-related topics, from preclinical research and clinical trials exploring novel therapies, to the socioeconomic dimensions of cancer care and initiatives improving access and equity, to patient and caregiver-led efforts in advocacy and policy. While this year’s AACR was no different in its scope, it made history in its execution: in light of COVID-19, AACR 2020 was held virtually and made free to attend (and of note, you can still register for and view it here).
AACR’s adaptation to our present circumstances aligns with its mission, as described by program chair Antoni Ribas, to “enhance communication of scientific breakthroughs”. In this same spirit, this post kicks off a series of “dispatches” that will highlight the cutting-edge research presented at AACR and its implications for the future of cancer treatment. In today’s dispatch, we explore how new ways of examining patients’ cancer cells could improve diagnostic testing and lead to better outcomes on personalized therapies.
Unraveling tumor cell biology with “personal regulomes”
Each of our cells, despite being smaller than a pencil tip, packs a whopping six feet of DNA. This is possible because our DNA is tightly compacted (and wrapped, spool-like, around clusters of proteins) in structures called nucleosomes. DNA compaction also has a role in gene expression–when a gene is expressed, its DNA sequence is loosened away from nucleosomes, allowing proteins called transcription factors to latch on and initiate the cascade of processes resulting in protein production. And DNA sequences encoding so-called regulatory elements, which affect the expression of nearby genes, are more open when the genes they act upon are being expressed. Because of all this, scientists can examine patterns of open and closed DNA to make inferences about a cell’s genetic repertoire. And, as Dr. Howard Y. Chang demonstrated in his AACR plenary talk, these patterns can also signal the presence of cancer.
Dr. Chang is the Director of the Center of Personal Dynamic Regulomes at Stanford. His lab is credited with inventing the ATAC-Seq assay, which sequences accessible, nucleosome light regions of the genome. Upon applying this assay to The Cancer Genome Atlas, a database of tumor samples and bioinformatic data from dozens of cancers, Dr. Chang and his colleagues discovered that they could predict whether a given sample was cancerous and even delineate different types of cancer from their distinctive patterns of accessible DNA. They also identified stretches of abnormally open DNA that were risk factors for cancer (including some associated with the cancer-driving gene Myc) and correlated with familial cancer susceptibility.
In subsequent work, ATAC-Seq was shown to detect another genetic anomaly in cancer: extrachromosomal DNA (ecDNA), an unnatural form of DNA that arises from errors in cell division and is estimated to exist in nearly half of all cancers. And because ecDNA frequently harbors extra copies of the genes cancer cells rely on, sequencing it could help guide decision-making for targeted therapies.
Altogether, Dr. Chang’s findings suggest that a snapshot of the accessible DNA in a patient’s cells, what he refers to as their “personal regulome”, can provide insight on their risk for developing cancer, detect and diagnose their cancer, monitor disease progression and response to treatment, and even suggest routes of personalized therapy. While traditional molecular diagnostic tests give a limited view of a tumor’s biology, scanning its DNA for one or a few cancer-associated mutations, the personal regulome is like a wide-angle lens, capturing a sweeping view of its oncogenic activities and, perhaps, revealing opportunities to defuse them.
Detecting methylation for earlier, less invasive diagnosis
Changes to DNA accessibility are far from the only indicator of a cell veering towards cancer. Methylation, a chemical roadblock deposited on DNA that “silences” or prevents gene expression, is another genetic feature that is noticeably altered in cancer cells. While DNA methylation is a normal occurrence and key to processes like stem cell differentiation, cancer cells sometimes misuse it to shut down genes known as “tumor suppressors”, effectively cutting the brakes on their proliferation and survival. In his plenary talk, Dr. Daniel D. De Carvalho proposed sniffing out cancer by its DNA methylation patterns, debuting an approach that could diagnose patients earlier and less invasively than current molecular tests.
Dr. De Carvalho, a scientist at Princess Margaret Cancer Centre and assistant professor at the University of Toronto, presented cfMEDip-Seq, a technique developed in his lab to sequence methylated circulating free DNA (cfDNA), or DNA that is present in the bloodstream. Though cfDNA can come from various types of cells, tumor cells release exceptionally high amounts of it, spurring cancer researchers to devise blood-based “liquid” biopsies as a noninvasive alternative to tissue biopsies. However, while the idea of diagnosing cancer from a blood test is undoubtedly appealing, in practice Dr. De Carvalho likens it to finding a needle in a haystack. Because these tests are designed to detect one specific cancer-associated mutation, the likelihood of catching a piece of tumor cfDNA carrying it can be quite low. One way of overcoming this could be to search for a cancer-associated marker found at many sites across the genome, such as DNA methylation.
To test this hypothesis, Dr. De Carvalho’s group brought their cfMEDip-Seq technique from the lab to the clinic, finding that it indeed could detect cancer from cfDNA in liquid biopsies. Moreover, it was sensitive and reliable with scant amounts of cfDNA, suggesting that it could diagnose cancer in its earlier stages, when tumors are sometimes too small to be picked up by traditional tests. Analysis of tumor DNA methylation profiles also yielded valuable clinical information–defining early versus late stage disease, predicting survival outcomes, and even reflecting changes in tumor size with treatment response or relapse. And this approach could pave the way for even less invasive liquid biopsies; in a study focused on urothelial cancers, Dr. De Carvalho’s group had similar success using cfDNA recovered from urine.
Altogether, these AACR talks proposed a pair of technologies, initially created in labs narrowing in on the epigenetics of cancer, for repurposing in the clinic. They showed their potential to detect tumors early, accurately, and noninvasively, and to uncover therapeutically useful biology in a single diagnostic test. And they suggested that, in the future, viewing cancer through new molecular lenses could bring better outcomes into focus.
Edited by Sara Musetti
Chang, Howard Y. Personal regulome navigation of cancer. Plenary session talk given at AACR (2020).
Buenrostro, et al. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature Methods 10, 1213–1218 (2013).
Corces, et al. The chromatin accessibility landscape of primary human cancers. Science 362, eeav1898 (2018).
Wu, et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 575, 699–703 (2019).
De Carvalho, Daniel D. Turning the science of epigenetics into novel cancer early detection, classification, and monitoring approaches Plenary session talk given at AACR (2020).
Shen, et al. Preparation of cfMeDIP-seq libraries for methylome profiling of plasma cell-free DNA. Nature Protocols 14, 2749–2780 (2019).
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