2023-05-10 17:00:03
Researchers have analyzed the complete genome of 7,108 patients (3 billion base pairs) to characterize the genomic differences between primary and metastatic cancers, the study in “Nature”, and quantify their impact on resistance to therapies in order to understand and take advantage of therapeutic interventions that establish more effective therapies and personalized, “Nature Genetics”.
This data set, obtained in collaboration with the Oncode Institute of the University of Utrecht and the Hartwig Medical Foundationencompasses more than 7,000 unmatched primary and metastatic tumor samples from 71 cancer types, including 23 cancer types with a large representation in both clinical stages.
His work has made it possible to determine, for example, that the type of tumor is decisive in the risk of metastasis. “In some types of tumors, such as pancreatic tumors, the genomic differences between primary and metastatic tumors are subtle. Meanwhile in In others, such as prostate, thyroid and some types of breast cancer, there are very important genomic differences»says Martinez.
In addition, such exhaustive analysis has made it possible to identify recurrent genomic patterns in metastatic tumors such as the presence of high genomic instability, the greater enrichment of structural genomic alterations versus point mutations, or the presence of genomic alterations associated with the acquisition of resistance to treatment. . However, hardly any conductive alterations exclusively associated with the metastasis process have been identified.
natural evolution
In this sense, explains Martínez, “our results confirm a large-scale trend in the field of metastasis research, and in which the metastasis process cannot be explained by a specific genomic alteration, if not, by an evolutionary process in which the interaction of tumor cells with the microenvironment surrounding the tumor possibly plays a very relevant role”.
This researcher explains that all tumors acquire plasticity and flexibility to adapt to different situations, such as treatment. Some, he adds, godropping‘ cells into the bloodstream and some of these can become located in other tissue and form metastases. And this is part of the evolution of the vast majority of tumors.
One in four patients has genomic alterations associated with the escape routes of the immune system
The results can help us understand why some primary tumors do not metastasize, due to their slow progression, or why there are so many differences between primary and metastatic cancers in breast or prostate tumors.
Thus, the comparison between primary and metastatic tumors revealed that there are hardly any differences between the two stages, neither in the frequency nor in the type of immune system escape alterations observed. «This leads us to believe that most tumors probably acquire the ability to evade the immune system very early in their evolution.».
In the study published in “Nature Genetics”, the cohort of more than 7,000 samples of complete tumor genomes previously described has been used to identify the prevalence of genomic alterations associated with escape from the immune system, as well as to determine if there are differences between primary and metastatic tumors. “We know that tumors have the ability to be invisible to the immune system, but we wanted to understand what genomic alterations confer this ability and how frequently we detect them in different types of cancer and at different stages of tumor evolution.”
Most tumors probably acquire the ability to evade the immune system very early in their evolution.
Francisco Martinez Jimenez
Vall d’Hebron Institute of Oncology
Research shows that 1 in 4 patients have genomic alterations associated with the escape pathways of the immune system. But with nuances: for example, in some, such as cervical carcinoma, more than half of the patients have these alterations; in others, the prevalence is practically nil.
Martínez explains that “if we are able to identify alterations that make them invisible to the immune system, we would have taken a very important step because the immune system exerts pressure on tumors to eliminate them, just as if it were a virus or a bacterial infection, etc.” .
Another aspect that these investigations will allow is to advance in determining which patients are going to have a higher probability of metastasis in order to carry out more targeted treatments. “This is one of the avenues that we have to continue, particularly in cancers where there are big differences between primary and metastatic tumors.”
Martínez concludes that these two studies allow us to better understand the fundamental genomic characteristics of metastatic tumors. This may open up new opportunities to stratify patients with primary tumors that from the beginning have genomic characteristics of more advanced tumors, as well as to identify new therapeutic alternatives aimed at treating the weaknesses of these tumors.
Finally, the data generated in these studies are public and available to the scientific community as a resource for cancer research. “We hope that this data set will be a resource that other groups use in their research and that it will eventually contribute to the development of better treatments for cancer patients,” concludes Martínez Jiménez.
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