Mutations occur in different tissues and organs of an individual. Somatic mutations occur in cells that will not give offspring and therefore are not passed on to subsequent generations. Caused by many factors such as age and smoking, somatic mutations are the main cause of cancer and play a role in other diseases as well.
A study led by ICREA researchers Dr. Fran Supek of the Institute for Research in Biomedicine (IRB Barcelona) and Dr. Ben Lehner of the Center for Genomic Regulation (CRG) has identified heritable genetic traits that predispose individuals to the appearance of specific types of somatic mutations in their tissues. People with higher mutation rates in an organ are more likely to build mutations in key cancer genes, which can increase the risk of tumor formation.
Researchers have previously described the hereditary mechanisms that predispose individuals to cancer, although many tumors have no clear genetic explanation. It is conceivable that the risk of cancer results from changes in the spectrum of different types of somatic mutations, a common cause of cancer.
“In this comprehensive study, we checked whether different types of changes in DNA seen in tumors were associated with heritable variants in many different genes. We developed a methodology that allowed us to identify 42 genes, related to 15 different cellular mechanisms, that influence the risk of different types of somatic mutations. This may help explain the risks of being predisposed to cancer,” explains Dr. Mischan Vali Pour, who led the study while a doctoral student in Dr. Lehner and Dr. supek.
“While some examples of genes responsible for changing patterns of somatic mutations, such as the BRCA genes that predispose to breast and ovarian cancer, and the Lynch syndrome genes that predispose to colon cancer, have been previously known, we now find many others. genes can similarly affect the accumulation of somatic mutations.” says dr. Fran Supek, head of the Genome Data Science Laboratory at IRB Barcelona.
Future work based on this study may help assess a patient’s hereditary risk of developing a specific type of cancer and thereby personalize their prevention program and/or detect the disease at an early stage. In addition, cancer treatments could potentially be personalized via somatic mutational signatures, as evidenced by: another recent study by the IRB Barcelona†
Genomic instability and the risk of cancer
Most of the mechanisms involved in the generation of mutations are related to defects in the repair of damaged DNA. This results in a phenomenon known as genomic instability, which shortens the time it takes for the 2 to 10 mutations in cancer driver genes to appear that are normally required for a tumor to develop.
Each of the identified mechanisms also produces different types of mutations, or in different regions of the genome, and may therefore be related to cancers arising in certain organs.
Statistical and machine learning methods
To make these predictions, the researchers developed a methodology based on statistical genomics and a machine learning model — the so-called “autoencoder” neural network — that can find patterns in complex data. The study analyzed 11,000 genome sequences of cancer patients of European descent.
One of the limitations of the study is the wide variability of heritable factors associated with somatic mutations and the relatively low prevalence of each of these factors individually. The number of available genome sequences limits the ability to discover links between genes and mutations. Access to more genomic data from cancer patients of non-European descent could lead to further findings.
“As more genetic data becomes available, additional genetic predisposing factors for cancer mutagenesis are likely to be found. The ‘rare’ genetic variants we considered here, although they each occur in only a few individuals, together are very important in shaping cancer genomes and potential cancer risk,” concludes Dr. Ben Lehner, head of the Genetic Systems Laboratory and CRG’s Systems Biology Coordinator.
This work received funding from the Spanish Ministry of Science and Innovation, the European Research Council (ERC), the Horizon2020 European Program, the Bettencourt Schueller Foundation, the AXA Research Fund, the Agency for the Management of University and Research Funds (Government of Catalonia), the EMBO YIP program, the Severo Ochoa Center of Excellence Award and the CERCA program (Government of Catalonia).
The impact of rare germline variants on human somatic mutation processes
Mischan Vali Pour, Ben Lehner & Fran Supek
Nature communication (2022). DOI: 10.1038/s41467-022-31483-1
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