A study published today in the journal\u00a0Science\u00a0reveals how jumping fragments of human DNA, a type of genetic parasite, destabilise the cancer genome. Unstable genomes are a fertile playground for cancer evolution, giving malignant cells more opportunities to grow, adapt and evade treatment.\u00a0<\/p>\n
The researchers analyzed genome sequences from tumors with unusually high activity of LINE-1 (L1) elements, fragments of DNA which copy themselves and paste that copy into other locations within the genome.\u00a0<\/p>\n
Previously thought to be a source of local mutations that occasionally disrupt individual genes when inserted into the wrong place, the researchers now find evidence that L1 activity can also drive large-scale architectural modifications which\u00a0seed genomic chaos.\u00a0<\/p>\n
“Cancer genomes are more influenced by these jumping fragments of DNA parasites than we previously thought,” explains\u00a0Professor\u00a0Jos\u00e9\u00a0Tubio, researcher at the Centro de\u00a0Investigaci\u00f3n\u00a0en\u00a0Medicina Molecular y\u00a0Enfermedades\u00a0Cr\u00f3nicas\u00a0(CiMUS) at the\u00a0Universidade\u00a0de Santiago de Compostela (USC) and coordinator of the study.\u00a0<\/p>\n
The findings challenge the long-held assumption that L1 activity is a byproduct of an already chaotic cancer genome. Rather than just\u00a0appearing in late stages of cancer, the study found two in three (65%) L1 events occurred during the\u00a0early stages\u00a0of tumor evolution.\u00a0<\/p>\n
The discovery could help explain how cancer reshapes the genome, and vice versa, at the\u00a0early stages\u00a0of the disease, knowledge which could eventually lead to new strategies for early detection and treatment.\u00a0<\/p>\n
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The next focus should be understanding when and where L1 activity tips the balance and how to target that therapeutically.”<\/p>\n
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Dr.\u00a0Bernardo Rodriguez-Martin, Independent Fellow at the Centre for Genomic Regulation in Barcelona and one of the main authors of the study<\/p>\n
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The legacy of ancient ‘DNA parasites’\u00a0<\/p>\n
L1 elements are ancient genetic hitchhikers. They are considered parasitic DNA sequences because\u00a0almost all\u00a0of them are either neutral or\u00a0deleterious\u00a0for the host organism, existing to promote their own replication through a process called retrotransposition.\u00a0<\/p>\n
For\u00a0many\u00a0million years of mammalian evolution, L1 elements have been amplifying in the genome. There are\u00a0roughly 500,000\u00a0copies which make up 17% of the human genome, but most are genomic fossils that lie dormant. On average,\u00a0each individual\u00a0has\u00a0a small fraction of\u00a0between 150 and 200 L1 elements which can still jump and insert themselves into new genomic locations.\u00a0<\/p>\n
L1 retrotransposition is known to be a frequent mutational process in\u00a0different types\u00a0of cancers, including head and neck,\u00a0lung\u00a0and colorectal tumors.\u00a0Early evidence\u00a0has shown\u00a0these events help\u00a0tumors grow and adapt by producing genomic\u00a0aberrations affecting cancer genes.\u00a0<\/p>\n
Exactly how L1 elements disrupt genomes, and to what extent they do so in health or disease has been unclear because much of what scientists could see depended on a technology called short-read DNA sequencing. When reading DNA, short-read technologies struggle to reconstruct how L1 elements alter the genome’s architecture.\u00a0<\/p>\n
To get around that, the researchers used\u00a0a new technology\u00a0called long-read sequencing. For the first time, this allowed them to see the full changes L1 elements make to the structure of the cancer genome, including deletions,\u00a0translocations\u00a0and other rearrangements to the DNA sequence.\u00a0<\/p>\n
One in 40 jumps rewire the genome\u00a0<\/p>\n
The researchers selected ten tumors with high L1 activity for in-depth sequencing: five head & neck squamous carcinomas, four lung squamous carcinomas and one colorectal adenoma. They found a total of 6,418 retrotransposition events, with variation between cancer types.\u00a0<\/p>\n
The vast majority of\u00a0copy and paste events found were insertions. These are instances where L1 elements insert a copy of themselves into the DNA sequence at other locations, altering the genome’s length. These events might interrupt a gene’s function, but most insertions are truncated and so unlikely to jump again.\u00a0<\/p>\n
Amongst these thousands of cases, the team also\u00a0identified\u00a0152 instances where L1 created large-scale structural rearrangements, with an incidence rate of 1 in 40 for tumors with high L1 activity and 1 in 60 for tumors with lower activity. These changes to the genome’s architecture are much more dramatic and disruptive, making them potentially powerful drivers of cancer development.\u00a0<\/p>\n
“On paper, 152 might not sound like\u00a0a huge number. But when\u00a0you’re\u00a0looking at just ten tumors,\u00a0that’s\u00a0extraordinarily high,” says\u00a0Rodriguez-Martin.\u00a0<\/p>\n
The finding matters because it strengthens arguments for using long-read sequencing in cases where standard tests cannot explain a tumor’s behavior, as short-read sequencing would not detect the possible mechanism of action.\u00a0<\/p>\n
“Three quarters of these large-scale rearrangements would have flown under the radar of short-read sequencing technologies. However, we expect the price of long-read sequencing to drop by\u00a0roughly half\u00a0this year alone, meaning this kind of deep structural analysis\u00a0won’t\u00a0remain niche for long,” says Dr. Rodriguez-Martin.\u00a0<\/p>\n
The structural rearrangements had many different mechanisms of action, including a DNA exchange between chromosomes that has been unknown to science until now. The researchers hypothesise it may be due to two separate L1 events that occur at\u00a0roughly the\u00a0same time on different chromosomes, with each swapping around the same amount of DNA in a balanced exchange they call a reciprocal translocation.\u00a0<\/p>\n
“It’s\u00a0as if two different pages of a book were torn simultaneously and fragments exchanged with each other. L1 elements behave like glue that sticks both pages together,” explains\u00a0Sonia\u00a0Zumalave, first author of the study.\u00a0<\/p>\n
New\u00a0clues\u00a0about early stages of tumor formation\u00a0<\/p>\n
A frequent early milestone of tumor formation is a whole genome doubling event, which happens when a cancer cell accidentally duplicates its\u00a0entire set\u00a0of chromosomes. Whole genome doubling occurred a median of 4.77 years before the diagnosis of the tumors used in the study.\u00a0<\/p>\n
The researchers found that most L1 activity preceded the whole genome doubling event, meaning retrotransposition can be an early mutational process. That suggests L1 activity is a bigger contributor to the genomic chaos that precedes cancer formation than previously thought.\u00a0<\/p>\n
In a side experiment, the study found that the promoters of L1 events are typically less methylated in tumors than in nearby non-tumor tissue, a pattern consistent with the idea that epigenetic changes to the human genome could\u00a0awaken\u00a0dormant parasitic DNA sequences.\u00a0<\/p>\n
There are limitations to the study. Its results are based on a deliberately chosen\u00a0set\u00a0of cancers with extreme L1 activity so that the scientists could detect rare mechanisms that would be invisible in samples with lower activity, meaning the findings may not apply to other types of tumors.\u00a0<\/p>\n
The study was carried out\u00a0by\u00a0the Centro de\u00a0Investigaci\u00f3n\u00a0en\u00a0Medicina Molecular y\u00a0Enfermedades\u00a0Cr\u00f3nicas\u00a0(CiMUS) at the\u00a0Universidade\u00a0de Santiago de Compostela\u00a0in collaboration with\u00a0the Centre for Genomic Regulation (CRG) in Barcelona, Universit\u00e9 C\u00f4te d’Azur in France,\u00a0the Francis Crick Institute in the United Kingdom, and\u00a0the University of Texas MD Anderson Cancer\u00a0Center\u00a0in the United States.\u00a0<\/p>\n
Source:<\/p>\n
Center for Genomic Regulation<\/a><\/p>\n Journal reference:<\/p>\n