Researchers are leveraging knowledge of genetic alterations in cancer to develop approaches that are driven by artificial intelligence for establishing comprehensive maps of somatic mutations across different cancer types. In a recent study, researchers developed a deep learning model that identified known and previously unknown somatic mutations as drivers of cancer development across 37 types of cancers (73). Characterizing cancers at a molecular level based on the types of genetic alterations, as well as understanding how genetic mutations contribute to cancer, has led to the development and FDA approval of many molecularly targeted therapies (74). Recent research efforts are focused on understanding how germline and somatic mutations work together to cause cancer, and whether this knowledge can be applied to find new ways to test for and Clonal hematopoiesis is a condition in which somatic mutations associated with blood cancers are detected when DNA from blood cells of healthy individuals is sequenced for other clinical reasons. Clonal hematopoiesis increases with age and is associated with an increased risk of developing blood cancer (72). What Are Genetic Alterations? Genetic alterations are changes in the DNA sequence. While not all genetic alterations cause cancer, many can result in downstream changes in the sequence or amount of mRNA and/or proteins produced, some of which can drive or contribute to cancer development. Genetic alterations are one of the hallmarks of cancer cells. HOW ARE GENETIC ALTERATIONS ACQUIRED? Cells can acquire genetic alterations in a number of ways, including: By inheritance from parents During a person’s lifetime from: • Certain viral infections • Smoking • Extended exposure to UV radiation • Exposure to mutagens or other cancer-causing chemicals • Errors made during cell division WHAT TYPES OF GENETIC ALTERATIONS CONTRIBUTE TO CANCER DEVELOPMENT? Single base changes Refers to deletion, insertion, or substitution of a single base (designated A, T, G, C) in DNA that can result in new proteins, altered versions of normal proteins, loss of protein function, or changed amount of the protein produced. Gene amplification Reflects extra copies of genes in the genome, causing higher quantities of certain proteins that can enhance cell survival and growth. Structural variations Arise when two separate genes or pieces of chromosomes join to produce a new protein or different amount of protein. Deletions Indicate loss of DNA, which can result in loss of genes necessary to regulate the processes that control normal cell growth, multiplication, and life span. In addition, recent findings have shown that many other types of changes to a cell’s DNA, such as the presence of extrachromosomal DNA (ecDNA)—particles of viral or self-DNA existing outside the genome—in human cells, also contribute to cancer development (see New Frontiers in Cancer Research, p. 143). It is important to note that not all genetic alterations contribute to cancer. Adapted from (67,68). SIDEBAR 7 AACR Cancer Progress Report 2023 Understanding the Path to Cancer Development 30
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