{"id":28965,"date":"2023-05-10T12:00:00","date_gmt":"2023-05-10T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2023\/extrachromosomal-dna-barretts-esophageal-cancer"},"modified":"2024-11-03T15:12:46","modified_gmt":"2024-11-03T15:12:46","slug":"coming-full-circle-on-cancer-and-extrachromosomal-dna","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/coming-full-circle-on-cancer-and-extrachromosomal-dna\/","title":{"rendered":"Coming Full Circle on Cancer and Extrachromosomal DNA"},"content":{"rendered":"

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\"A <\/div>
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A scanning electron micrograph of a cancer cell nucleus showing chromosomes (blue arrows) with ecDNA (orange arrows) scattered around them.<\/p>\n

Credit: Image used courtesy of Dr. Paul Mischel<\/p>\n<\/p><\/div>\n<\/figcaption><\/figure>\n<\/p><\/div>\n

A new study has brought researchers a step closer to understanding the role an unusual form of DNA can play in cancer. This form of DNA<\/a>\u2014called extrachromosomal DNA (ecDNA)\u2014doesn\u2019t reside on chromosomes<\/a>, the long tendrils of tightly packaged DNA found inside the nucleus<\/a> of cells. Instead, circular ecDNA particles float around the nucleus like a child\u2019s lost inner tube in a swimming pool. <\/p>\n

A series of recent studies have linked ecDNA to cancer\u2014namely, finding that its presence may help tumors become resistant to treatments and reduce how long people with cancer live. In this new study, researchers wanted to see if ecDNA could be found before cancer had set in. To do so, they focused on esophageal cancer and a condition called Barrett\u2019s esophagus<\/a>. In a very small percentage of people, Barrett\u2019s esophagus develops into cancer.<\/p>\n

The research team\u2019s analyses didn\u2019t prove that ecDNA in Barrett\u2019s esophagus causes esophageal cancer. But they provided the strongest evidence to date that ecDNA directly influences the initial formation and continued progression of esophageal cancer<\/a>. <\/p>\n

For example, they showed for the first time that ecDNA is indeed present in precancerous<\/a> tissue and not just cancer cells. And the analyses strongly suggested that when ecDNA is present in precancerous tissue, then that tissue is almost certain to become cancer\u2014at least in the case of Barrett\u2019s esophagus.<\/p>\n

Other key findings included that ecDNA volume in tumors increased as they progressed from early to late stages and that the circular DNA often had an array of cancer-causing genes, known as oncogenes<\/a>.<\/p>\n

Published April 13 in Nature<\/em>, the study was funded through a collaborative initiative between NCI and Cancer Research UK called Cancer Grand Challenges (CGC)<\/a>. The CGC\u2019s goal is to support large research teams that will address some of the most challenging problems in cancer.<\/p>\n

\u201cI think [this study] has taught us some important biological lessons,\u201d said one of the study\u2019s lead investigators, Paul Mischel, M.D., of the Stanford University School of Medicine. \u201cThe first is that it takes away this idea that ecDNA is a late comer [in the development of cancer]\u2026. No, it can arise early.”<\/p>\n

Although the study looked specifically at esophageal cancer and Barrett\u2019s esophagus, its findings, along with those from other recent studies of ecDNA, strongly suggest that ecDNA is directly involved in the development of many other cancers, said Ian Fingerman, Ph.D., of NCI\u2019s Division of Cancer Biology<\/a>. <\/p>\n

Although further studies are needed, Dr. Fingerman continued, \u201cThere\u2019s no reason to think that may not be the case.\u201d<\/p>\n

ecDNA and cancer<\/h2>\n

The DNA in most human cells is housed on 23 pairs of chromosomes that reside in the nucleus. <\/p>\n

In the 1960s, scientists discovered the existence of large snippets of DNA in the nucleus of cancer cells that appeared to have been jettisoned from chromosomes. Interest in this floating DNA among researchers never really took hold, at least until the 2010s, said Dr. Mischel, one of the first researchers to identify ecDNA as a potential contributor to cancer.<\/p>\n

During the last 5 to 10 years, however, thanks to technological leaps\u2014including whole-genome<\/a> sequencing, advanced imaging<\/a>, and sophisticated computational tools\u2014researchers have been able to unlock some of ecDNA\u2019s secrets. For example, although there were clues that ecDNA is circular, it wasn\u2019t until 2019 that a study led by Dr. Mischel confirmed that it forms a ring shape<\/a>.<\/p>\n

Some of the same studies linking ecDNA\u2019s presence to tumor resistance to certain cancer treatments<\/a> and shorter survival<\/a> have also found that they frequently contain oncogenes, and often many copies of those oncogenes (known as amplification).<\/p>\n

That\u2019s particularly important, Dr. Mischel explained, because previous studies he helped lead have shown that, by virtue of their round shape, ecDNA can more rapidly ramp up the activity of these cancer-causing genes<\/a> and to a greater degree than chromosome-bound genes. <\/p>\n

He also stressed another important point about ecDNA. Because ecDNA aren\u2019t attached to chromosomes, they aren\u2019t evenly distributed during cell division<\/a> like chromosomes and their DNA cargo. Rather, they are randomly parceled to cancer cells as those cells divide and grow in number. As a result, \u201ctumors can reach very high levels of cancer-causing genes\u2026 and achieve high levels of genetic variability,\u201d he said.<\/p>\n

\nCredit: Nature Genetics. September 2022. https:\/\/doi.org\/10.1038\/s41588-022-01177-x. CC BY 4.0.” data-embed-button=”cgov_image_button” data-entity-embed-display=”view_mode:media.image_display_article_full” data-entity-type=”media” data-entity-uuid=”e1bd563b-fa5f-464a-bf32-85f657d2d9ad” data-langcode=”en” class=”embedded-entity align-left”> <\/p>\n
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\"Five<\/div>
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Live-cell time-lapse imaging showing how, during cancer cell division, ecDNA (green dots) aren\u2019t evenly distributed in the resulting “daughter cells.”<\/p>\n

Credit: Nature Genetics. September 2022. https:\/\/doi.org\/10.1038\/s41588-022-01177-x. CC BY 4.0.<\/p>\n<\/p><\/div>\n<\/figcaption><\/figure>\n<\/div>\n

But even with these findings, the extent of ecDNA\u2019s direct involvement in cancer has been unclear. According to Dr. Fingerman, one big question has been whether they are a root cause of cancer or if they only emerge once \u201cgenomic instability<\/a>\u201d has set in, cell division has gone totally awry, and tumors have formed.<\/p>\n

From Cancer Grand Challenges to Barrett\u2019s esophagus and esophageal cancer<\/h2>\n

Dr. Mischel leads an international team of researchers who were one of the first four groups to receive CGC funding in 2022. The CGC initiative \u201cput in place the kind of framework that allows for this kind of ambitious team science,\u201d Dr. Mischel said. <\/p>\n

With their sizable funding award came the task of helping answer the key unresolved questions around ecDNA<\/a>. Barrett\u2019s esophagus and esophageal cancer offered an ideal opportunity to do just that, he continued.<\/p>\n

Although Barrett\u2019s esophagus is a precancerous condition, brought on by long-standing gastroesophageal reflux<\/a>, it only progresses to esophageal cancer in about 1% of the people who have it. It also appears to progress in distinct stages, with the tissue in the esophagus undergoing abnormal physical changes that trace a path: from low-grade dysplasia<\/a> to high-grade dysplasia to full-blown cancer.<\/p>\n

For this study, the CGC team joined with colleagues from Cambridge University Hospital in the United Kingdom and Fred Hutchinson Cancer Center in Seattle who, as part of long-term studies, had a valuable trove of tissue samples from people with Barrett\u2019s esophagus and esophageal cancer. The Fred Hutchinson team, in fact, had multiple samples that had been collected over several years or longer from people whose Barrett\u2019s developed into cancer and in whom that progression hadn\u2019t occurred.<\/p>\n

This latter bunch of samples, Dr. Mischel explained, provided a unique chance to learn from patients by performing a before-and-after examination\u2014a pre- and post-cancer\/no cancer time window\u2014in which they could home in specifically on ecDNA.<\/p>\n

First indications that ecDNA can fuel cancer<\/h2>\n

The Cambridge group had 200 samples from people with Barrett\u2019s esophagus and esophageal cancer. Whereas the Fred Hutchinson group provided samples from 40 people with Barrett\u2019s that progressed to cancer and from 40 in which it didn\u2019t.<\/p>\n

When the researchers looked across samples from both groups, no ecDNA was found in any from people with Barrett\u2019s esophagus that had low-grade dysplasia. But in Barrett\u2019s esophagus with high-grade dysplasia, it was a different story.<\/p>\n

In the Fred Hutchinson samples, for example, every person with high-grade dysplasia that had ecDNA went on to develop cancer. By contrast, among the people whose Barrett\u2019s esophagus with high-grade dysplasia that did not go on to become cancer, only one had ecDNA, and in only a single sample. That person died from another cause. <\/p>\n

Further, the frequency of ecDNA (and its level of oncogene amplification) increased as tumors progressed from early-stage to late-stage cancers. In the Cambridge samples, for example, 25% of early-stage esophageal cancer samples had ecDNA, compared with 43% of late-stage samples. In addition, the amount of ecDNA in cells was much higher in the late-stage esophageal cancer samples than in the early-stage samples.<\/p>\n

Another key finding came from the small group of samples from people who went on to develop cancer: a strong link between the presence of ecDNA and alterations in a gene known as TP53<\/em>. <\/p>\n

Often referred to as the \u201cGuardian of the Genome,\u201d TP53<\/em> is one of the most important tumor suppressor genes<\/a>. It directs activity that can repair damaged DNA in healthy cells or, if DNA damage is too extensive and uncontrolled cell growth is likely, push cells toward death. Alterations to TP53, however, can prevent it from performing these duties.<\/p>\n

Changes in TP53<\/em> were present in all eight of the people who went on to develop cancer and in whom ecDNA were found prior to their cancer diagnosis, they reported.<\/p>\n

The consistent finding of TP53<\/em> alterations in this group, Dr. Mischel said, suggests that this change \u201cis critical to \u2018setting the soil\u2019 in which ecDNA can arise.\u201d <\/p>\n

Further analyses, other cancers<\/h2>\n

The research team is performing new analyses to follow-up on several potentially important clues in the existing data, Dr. Mischel said. Those analyses include looking more closely at the events that led to ecDNA formation and at the activity of other cancer-related genes in ecDNA. They\u2019re also developing similar studies for other cancers.<\/p>\n

As for esophageal cancer, the study\u2019s findings are unlikely to have an immediate impact, wrote David Wang, M.D., who specializes in treating this cancer at the University of Texas Southwestern Medical Center, in an accompanying editorial in Nature<\/em>. <\/p>\n

Dr. Wang agreed that the study\u2019s findings point to an important role for ecDNA in the progression from Barrett’s esophagus to esophageal cancer. But, he noted, further studies are needed to determine how to apply what\u2019s known so far about ecDNA to better combat the disease.<\/p>\n

\u201cFuture work,\u201d he wrote, \u201cshould focus on therapeutic interventions relating to [ecDNA].\u201d<\/p>\n

While treatment improvements are a clear possibility as researchers learn more about ecDNA, Dr. Mischel agreed, this work also may present other clinical opportunities.<\/p>\n

\u201cWe \u2026 need to think about the potential [of using ecDNA] for [cancer] early detection and surveillance<\/a> strategies,\u201d Dr. Mischel said. \u201cThere [are] real opportunities here to begin looking at these things.\u201d<\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

May 10, 2023, by Carmen Phillips A scanning electron micrograph of a cancer cell nucleus showing chromosomes (blue arrows) with ecDNA (orange arrows) scattered around them. Credit: Image used courtesy of Dr. Paul Mischel A new study has brought researchers a step closer to understanding the role an unusual form of DNA can play in […]<\/p>\n","protected":false},"author":2,"featured_media":28966,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-28965","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28965","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=28965"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28965\/revisions"}],"predecessor-version":[{"id":42958,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28965\/revisions\/42958"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media\/28966"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=28965"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=28965"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=28965"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}