The genes we are born with also influence the origin and development of cancer.

An international study led by Mount Sinai experts has warned that inherited genes play a key role in the production of tumor-associated proteins. They warn that, because of this, cancers evolve differently in each patient.

                                                                                           

Cancer is the leading cause of death worldwide. In 2022, according to the World Health Organization (WHO), nearly 10 million deaths were recorded from this disease, representing one in six deaths. In the Americas, according to the Pan American Health Organization (PAHO), that same year, there were more than 4.2 million new cases, of which 1.4 million died, almost half of whom were people under the age of 70. Now, a recent study led by experts from the Icahn Institute at Mount Sinai has revealed how genes inherited from birth have a direct impact on the development of tumors. According to a statement issued by the Icahn School of Medicine at Mount Sinai, this work, conducted in collaboration with the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and funded by the National Cancer Institute, identified that germline genetic variants, i.e., those with which we are born, play a crucial role in the evolution of tumors. This finding challenges the traditional approach that prioritizes somatic mutations, or simply put, genetic changes acquired throughout life, and opens up new possibilities for personalized cancer treatments.

The study, published in the journal Cell, could mark a turning point in the understanding and treatment of cancer, as it focuses on how germline variants, which are present in DNA from birth, far outnumber and significantly outnumber somatic variants. This discovery not only expands knowledge of cancer biology but could also significantly improve diagnosis, risk prediction, and the selection of personalized therapies.

                                                      

                                                                               

  

To understand this, the study analyzed data from more than 1,000 patients with 10 different types of cancer. In the words of Dr. Zeynep H. Gümüş, co-author of the study, these variants, which are present from birth, "are not just secondary, but can play an active role in tumor formation, its evolution, and even its response to treatment." This approach could transform precision medicine, especially given that the PAHO (National Health Organization) states that cancer cases worldwide could increase by 60% by 2045, reaching 6.7 million cases.

But that's not all, as this advance modifies a central element of molecular oncology. Until now, cancer treatments focused primarily on the genetic profile of the tumor, that is, the changes acquired by cancer cells. The new study shows that inherited genetic variants, which are part of each individual's DNA from birth, significantly influence tumor behavior, progression, and response to treatment.

According to the authors, this approach would improve risk prediction, personalize treatments, and understand why two patients with the same tumor type can have very different responses. It would also redefine precision medicine in oncology, which would no longer focus exclusively on the tumor itself, as diagnoses and treatments could also be tailored to the patient's inherited genetics.

                                                                                         

  

The Role of Germline Variants in Cancer

The study used an advanced technique known as precision peptidomics to analyze how inherited genetic variants affect the structure, stability, and function of proteins in tumor cells. According to the Icahn School of Medicine at Mount Sinai, more than 330,000 germline variants that code for proteins were mapped.

 In other words, they were able to identify how these variations modified protein production and function in tumors. These variations affect not only protein structure but also their stability, abundance, and subsequent modification—critical elements in cancer behavior. In this way, they were able to identify how these differences can determine the interaction of tumors with the immune system.

 “Our study revolutionizes the landscape by demonstrating that hereditary changes in DNA can influence gene expression and protein production and modification—key factors in cancer behavior—in tumors,” Gümüş said. Meanwhile, Dr. Myvizhi Esai Selvan, co-senior author of the study, explained that "in the evolution of cancer, the inherited genome sets the stage. It helps determine which mutations are important, how aggressive a tumor might become, and how the immune system will respond."

                                                                                             

 

This approach allows for a better understanding of the wide variations that doctors observe in the onset, progression, and response of cancer to therapies in different patients. “Each person carries a unique combination of genetic variants from birth, and these inherited differences quietly shape how our cells function throughout life,” Gümüş said in a press release.

 To illustrate the magnitude of the finding, the researchers detailed that germline variants can influence key processes such as post-translational modification of proteins, protein stability, and gene expression. To explain this set of terms, a useful analogy is to imagine that inherited DNA acts as an “instruction manual” that determines how proteins are assembled and function in the body. These proteins are essential for performing all of the body's functions, such as building tissues, transporting oxygen, defending against infections, or regulating metabolic processes.

 If this manual contains errors or variations, proteins may not assemble correctly, which can alter their function and cause problems in cells, promoting the development of diseases. In this case: cancer. Furthermore, the study identified that these variants can have specific effects depending on the type of tumor and the patient's genetic ancestry.

                                                                                       

For example, individuals of African descent had a higher average number of exonic variants—changes in the parts of DNA that code for proteins—compared to those of European descent. However, the researchers cautioned that most of the data analyzed came from patients of European descent, so further research will be needed to ensure the findings are applicable to more diverse populations.

 Implications for Precision Medicine and Future Research

The results of this study have the potential to revolutionize personalized cancer care. According to Dr. Gümüş, “These variants help explain some of the broad differences physicians see in the onset, progression, and response of cancer to therapies in individual patients.” This means that, in the future, physicians could use a patient's inherited genetic profile to design more effective and targeted treatments.

 "What we have shown is that these variants are not just secondary, but can play an active role in tumor formation, its progression, and even its response to treatment. This opens up new possibilities for personalizing cancer care, based not only on the tumor itself, but also on the patient's underlying genetic makeup," Gümüş emphasized.

                                                                                    

“This is a major step toward precision medicine that considers the whole individual, not just the cancer,” said Myvizhi Esai Selvan, co-senior author of the study and instructor of Genetics and Genomics at the Icahn School of Medicine at Mount Sinai. He added, “In cancer evolution, the inherited genome sets the stage. It helps determine which mutations are important, how aggressive a tumor might become, and how the immune system will respond.”

 In this regard, the research team is already working in two key areas: cancer immunotherapy and lung cancer risk prediction. In the first case, in collaboration with the National Cancer Institute's Centers for Cancer Immune Monitoring and Analysis, scientists are investigating why some patients respond well to immunotherapy while others do not. According to the statement, inherited genetic differences could be the key to understanding this variability.

                                                                                             

On the other hand, regarding lung cancer risk prediction, which is carried out through the Mount Sinai Million Health Discovery Program and the Million Veterans Program, computational models are being developed to predict its possible onset based on each person's genetic profile. These tools could be essential for identifying those who would benefit most from early detection, thereby improving clinical outcomes.

The study also highlights the importance of considering the impact of germline variants in comprehensive cancer care, since, according to the researchers, they not only influence tumor biology but also factors such as the immune system's response and interaction with the tumor microenvironment.

Despite the progress made, the study authors acknowledge that much research remains to be done: the group analyzed, although large, is not representative of all populations, and it will be crucial to expand the studies to include individuals of different genetic ancestries, in addition to validating these findings in larger clinical trials.