Two studies published today in Nature and Nature Genetics compare the complete genome of more than 7,000 primary and metastatic tumours and describe the global genomic differences between them, as well as their interaction with the immune system

Metastatic spread involves the detachment of tumour cells from a primary tumour, colonisation of secondary tissue and growth in a hostile environment. Advanced metastatic tumours are often able to withstand aggressive treatment regimens and represent the leading cause of cancer-associated death. “Despite many efforts to understand these phenomena, we still have limited knowledge of the contribution of genomic changes to metastasis,” says Francisco Martínez Jiménez, first author of the two studies published today in Nature and Nature Genetics, which he developed at the Centre for Molecular Medicine at the University of Utrecht, and current head of VHIO’s Computational Immunogenomics Group as well as leader of the Data Mining unit of the Hartwig Medical Foundation.

“It is therefore essential to characterise genomic differences between primary and metastatic cancers and quantify their impact on resistance to therapies in order to understand and exploit therapeutic interventions that establish more effective and personalised therapies.”

To address these questions, researchers from the Centre for Molecular Medicine and Oncode Institute at Utrecht University and the Hartwig Medical Foundation have generated the largest harmonised complete genome sequencing dataset of tumour genomes from cancer patients. This dataset covers more than 7,000 unpaired primary and metastatic tumour samples from 71 cancer types, including 23 cancer types with a large representation in both clinical stages.

Identifying genomic clues to metastasis

“One of the major problems we have encountered is that in recent years tumours have been analysed and sequenced with completely different analysis protocols, which makes an integrated analysis of the data very difficult. In this work we have processed the complete genome sequencing of more than 4,000 metastatic tumours, most of them previously treated, and reanalysed 2,500 untreated, early-stage, independent primary tumour samples with the same protocol. In total we have pooled data from 7,108 tumour samples from patients with a wide range of cancer types,” says the researcher.

The analysis of genomic differences between primary and metastatic tumours has led the researchers to several conclusions. “If I had to choose only one of the differences we have found, it would be that the differences are highly dependent on the type of tumour. In some types of tumours, such as pancreatic cancer, the genomic differences between primary and metastatic tumours are subtle. While in others, such as prostate, thyroid and some types of breast cancer, there are very important genomic differences,” says Dr Francisco Martínez Jiménez.

In addition, the exhaustive analysis has allowed us to identify recurrent genomic patterns in metastatic tumours such as the presence of high genomic instability, 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 driver alterations exclusively associated with the metastatic process have been identified.

“In this sense”, explains Dr Martínez, “our results confirm a dominant trend in the field of metastasis research on a large scale, in which the process of metastasis cannot be explained by a specific genomic alteration, but rather by an evolutionary process in which the interaction of tumour cells with the microenvironment surrounding the tumour possibly plays a very relevant role.”

However, this study has identified a set of genomic alterations that are enriched in metastatic tumours and may be associated with the acquisition of resistance to certain cancer treatments. “It is an important first step, but dedicated clinical studies are needed to validate its clinical relevance in patients,” concludes the researcher.

Genomic alterations in the tumour that allow it to escape the immune system.

In parallel, researchers have studied how tumours are able to escape the surveillance imposed by the immune system at different stages of the disease. This ability to escape often involves tumour-specific genomic alterations in immune-related pathways. In the study now published in the journal Nature Genetics, researchers have used the cohort of more than 7,000 whole genome samples from tumours described above to identify the prevalence of genomic alterations associated with immune escape, as well as to determine whether there are differences between primary and metastatic tumours. “We know that tumours have the ability to be invisible to the immune system, but we wanted to understand which genomic alterations confer this ability and how frequently we detect them in different types of cancer and at different stages of tumour progression.”

The results of this analysis revealed that one in four patients has genomic alterations in the tumour that are directly associated with escape from immune recognition. However, the researchers have again found substantial differences between different types of cancer, while in some, such as cervical carcinoma, more than half of the patients have these alterations; in others the prevalence is practically nil.

On the other hand, the comparison between primary and metastatic tumours revealed that there are hardly any differences between the two stages, either in the frequency or in the type of immune system escape disorders observed. “This leads us to believe that most tumours probably acquire the ability to evade the immune system at very early stages of their evolution,” explains Dr Francisco Martínez Jiménez.

Another feature found in this analysis is that the type and frequency of escape gene alterations is directly related to the number of mutations in the tumour (i.e. the number of changes in the DNA sequence of the tumour genome). In tumours with a low mutational load, virtually no escape gene alterations are observed, whereas in tumours with a medium and high mutational load, alterations that partially truncate recognition by the immune system are frequently observed. Finally, tumours with very high mutational load (commonly referred to as hypermutated or ultra-hypermutated) have a very specific type of alteration that tends to completely truncate recognition by the immune system.

“Now that we have a more complete picture of the landscape of escape gene alterations that make the tumour invisible to the immune system, the next step is to investigate whether these alterations have an influence on the immunotherapy treatment response,” says the head of VHIO’s Computational Immunogenomics Group and first author of the paper.

These two studies published in the journals Nature and Nature Genetics give us a better understanding of the fundamental genomic characteristics of metastatic tumours. This may open up new opportunities to stratify patients with primary tumours that have genomic characteristics of more advanced tumours from the outset, as well as to identify new therapeutic alternatives aimed at treating the weak points of these tumours. 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 dataset will be a resource for other groups to use in their research and eventually contribute to the development of better treatments for cancer patients,” concludes Dr Martínez Jiménez.

References

Francisco Martínez-Jiménez, Ali Movasati, Sascha Remy Brunner, Luan Nguyen, Peter Priestley, Edwin Cuppen, Arne Van Hoeck. Pan-cancer whole genome comparison of primary and metastatic solid tumors. Nature. 2023, May. DOI: 10.1038/s41586-023-06054-z.

Francisco Martínez-Jiménez, Peter Priestley, Charles Shale, Jonathan Baber, Erik Rozemuller, Edwin Cuppen. Genetic immune escape landscape in primary and metastatic cancer. Nature Genetics, 2023 May. DOI: 10.1038/s41588-023-01367-1