Cancer researchers have identified five main patterns of protein-altering mutations in tumors, known as amino acid substitution signatures, that play a significant role in how cancers interact with the immune system. This discovery is based on an analysis of nearly 9,300 cancer genomes from various types of cancer.
Mutations in cancer cells occur when DNA is damaged by environmental factors such as tobacco smoke or ultraviolet light, or through internal replication errors. These mutations alter the amino acids that make up proteins. The study found that rather than being random, most tumors display one of five characteristic mutation patterns.
These patterns not only reveal how the mutations originated but also affect whether the immune system can detect and respond to the tumor. Some mutation signatures produce protein fragments called neoantigens that are easily recognized by immune cells, making tumors more visible to the immune system. Other patterns result in fewer recognizable neoantigens, allowing some cancers to evade detection.
"Despite the diversity of mutational processes, their protein-level consequences converge into just five recurring fingerprints, which can strongly influence immune recognition," said Dr. Szilvia Juhász, Head of the Cancer Microbiome Research Group at HCEMM and one of the study's lead authors.
The research highlighted a particular mutation pattern associated with DNA repair defects and chemical exposures. Tumors dominated by this pattern often do not respond well to immune checkpoint inhibitor therapies even if they have a high number of mutations overall. This suggests that simply counting mutations does not predict treatment success; it is important to consider what kinds of proteins those mutations produce.
"Mutational burden alone is insufficient. Qualitative, protein-level consequences of mutations are critical for understanding why immunotherapy fails in many patients," emphasized Dr. Benjamin Papp, researcher at the HUN-REN Szeged Biological Research Centre and co–first author of the study.
The findings also indicate that genetic differences among patients can affect how well their immune systems recognize mutated proteins from tumors. For example, certain HLA class I types common among Europeans may help present these mutated peptides more effectively to T cells, making some tumors more detectable depending on a patient’s genetics.
Dr. Máté Manczinger, Head of the Systems Immunology Research Group at HUN-REN Szeged Biological Research Centre and senior author of the study stated: "Tumour visibility to the immune system is not determined by mutation numbers alone, but also by the protein-level patterns those mutations create." He added: "These findings support a new framework for truly personalized immunotherapy, integrating tumor genomics with the patient's immunogenetic background."
Researchers say these insights could improve predictions about who will benefit from immunotherapy treatments and reduce unnecessary procedures and side effects for patients.
The work was conducted through collaboration between several research groups including those at HUN-REN Szeged Biological Research Centre and HCEMM Cancer Microbiome Research Group. Funding came from sources such as an H2020 Teaming Grant involving Semmelweis University and international partners like European Molecular Biology Laboratory in Germany as well as awards from Hungarian Government programs.
