The largest study of cancer genomic aberrations shows how to tackle the most lethal tumors

The aberration involving a cancer cell would be equivalent to a copy of the Quixote that it started the other way around (“emradroca oreiuq on erbmon oyuc ed ,ahcnaM al ed ragul nu nE”), whose central character were actually seven knights-errant and that one of them had nine heads on his shoulders; where the trip to Barcelona was reversed and the protagonist charged against the windmills 500,000 times, over millions of pages. This unthinkable perversion is perfectly possible inside a cancer cell.

For decades, scientists have known that this disease not only causes mutations or misprints of a single letter in our genome – for example, an A for a C in a book made up of 3,000 million of those perfectly ordered letters – but also distorts its large-scale organization.

Our genome is perfectly organized in 23 chapters, the chromosomes, but tumors multiply some, delete others, spell complete parts backwards or repeat passages without stopping. These transformations provide the molecular machinery for tumors to grow much faster than healthy tissue, escape the immune system and become untouchable for some cancer therapies. These lesions, called genomic instability, are present in almost all types of tumor and in 100% of metastases, the cause of 90% of all cancer deaths. Whoever manages to understand and eliminate this crazy genomics will be able to stop the most lethal tumors.

Today the most complete study to date of the causes of these genomic aberrations of cancer is published. Almost 7,000 tumors of 33 different types have been studied. The results identify 17 patterns of large-scale genomic damage with important implications in the diagnosis and treatment of patients with a worse prognosis. A second study analyzes more than 9,000 tumors and details 21 similar aberrations. Both analyzes are published in the journal Natureworld science elite.

“We are beginning to see some logic in the midst of the madness,” summarizes Geoff Macintyre, computational biologist at the National Cancer Research Center (CNIO) and co-author of one of the studies. “Tumors with less survival, such as those of the ovary, pancreas, esophagus, lung or brain glioma, have a high degree of genomic instability. Until now, it has not been possible to understand the consequences of this genomic chaos because it is different in each patient. In this case we do not study the consequences, but the causes”, explains this 41-year-old Australian researcher.

The 17 patterns identified are universal, regardless of where the tumor is. The first is an unequal distribution of chromosomes among cancer cells, with some losing chapters while others carry them twice. The second provokes repetitions and consecutive amputations: “In one place in La Mancha, in one place in La Mancha, old shield, skinny hack and running greyhound, old shield, skinny hack and running greyhound”. These patterns are like evolutionary tests that end up generating a tumor that is difficult to kill.

The CNIO researcher Barbara Hernando realized that these delusional patterns reveal molecules and mechanisms absent in healthy cells that can be attacked with already known drugs. This 33-year-old molecular biologist from Castellón, winner of several gold medals in Spain in the pentathlon, has compiled up to 44 examples of therapies aimed at genetic errors in cancer that are already approved for a specific type of tumor and that could also be used against tumors of poor prognosis with one or more patterns of instability.

Those responsible for the study, in which the National Cancer Institute of the United Kingdom has also participated, also show that the patterns predict how the tumors will evolve and if they will be vulnerable to platinum compounds, a type of chemotherapy. “These biomarkers open up the possibility of universally applying cancer therapies,” summarizes Hernando.

Scientist Abel González, from the Barcelona Biomedical Research Institute, coordinates a 10-million-euro European project to characterize all the small-scale genetic changes —one-letter errors— found in each tumor in the hope of improving treatment. “This new study goes a step further because it provides biomarkers at a large genomic scale with which to approach the diagnosis and treatment of cancer more generally”, he highlights.

The future would be to give the same drug against many different types of tumor. There are already some examples, such as an immunotherapy that is given if a patient has a particular mutation, regardless of where their tumor is, or PARP inhibitors, initially targeting one mutation in ovarian cancer but being tested in other classes of tumors that have the same defect.

“Many times the causal mutations of cancer are sought and they are not found,” explains Andrés Aguilera, National Genetics Prize winner. “These new genomic instability profiles would make it possible to identify tumors that are susceptible to drugs designed for patients in whom these mutations are known. But the success probably depends a lot on the tumor of each one, ”he thinks.

In 2020, the largest genomic study on cancer opened the door to detecting a tumor before it appears, by locating dangerous causal mutations. Macintyre was one of the authors of that work. “If we really want to cure cancers with high genomic instability, we have to intervene before they happen,” he now explains.

Ovarian cancer is a brutal challenge, since the disease hardly presents external symptoms and the first mutations occur 20 years before diagnosis. Something similar happens with pancreatic cancer. Macintyre’s next objective is to try to get ahead of lung cancer by analyzing a few cells extracted during diagnostic tests such as bronchoscopy that could alert to a causal mutation. What to do then, if the patient does not yet have cancer? “We don’t know,” acknowledges the scientist, who has founded a company to develop some of his findings. Perhaps it is the beginning of a new way of administering chemotherapy in much smaller and more localized doses. The challenges that remain to be overcome are enormous, but the hope is that “every time we look at the genomic instability of a tumor everything begins to make sense”, he celebrates.

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