have developed several small molecular inhibitors that successfully inhibit the activity of the mutant KRAS in patients with NSCLC. One of the compounds, sotorasib (Lumakras), was approved by FDA in May 2021 (4), and a second compound, adagrasib (Krazati), was approved in December 2022 (see Expanding Treatment Options for Patients with Lung Cancer, p. 83). Basic research provides the foundational knowledge about what triggers cancer development; how cancer evades the body’s defenses; and how cancer spreads within the body, among other aspects of cancer biology (see Cancer Development: Interpreting Knowledge, p. 29). Basic research is also fueling the development of molecules that can help visualize cancer cells better, deliver drugs to tumors more precisely, and kill cancer cells more selectively and effectively. Collectively, basic research-driven advances are contributing to progress against cancer that is saving lives and improving health outcomes for countless patients. Cancer Development: Interpreting Knowledge At a fundamental level, cancer is a genetic disease that is caused by changes in genes that control vital functions, such as cell multiplication and cell growth (see Sidebar 7, p. 30). However, transformation of normal cells into cancer cells, accumulation of cancer cells to form tumors, and spread of tumors to distant sites in the body are all complex, multistep processes that are influenced by alterations inside the cell as well as changes outside the cell. Changes That Contribute to Cancer Initiation Cellular functions are dictated by instructions that are encoded in deoxyribonucleic acid (DNA), a complex molecule that constitutes the genetic material of cells. Four unique molecules or bases, designated A, T, C, and G, make up a DNA strand, and two DNA strands are then paired together to form a double helix. The entirety of a person’s DNA is called the genome. Inside the nucleus of human cells, the DNA double helix is wrapped around bead-like structures called nucleosomes, which are composed of proteins called histones. The packaged DNA is further compacted in multiple layers, making up structures we know as chromosomes. Nearly all human cells have 46 chromosomes. Genes are pieces of DNA and there are hundreds to thousands of genes contained in each chromosome. Genes carry instructions or messages for making proteins, which are functional units of the cell. The cell uses a complex process, called transcription, to copy the message embedded in a gene to make another type of molecule called messenger ribonucleic acid (mRNA). The information in mRNA is subsequently “translated” into proteins. Cellular needs influence how much mRNA or protein will be produced. The following section describes the types of changes within a cell that impact cancer development. Genetic Alterations Alterations in the DNA sequence, referred to as mutations, can disrupt or modify normal protein function and are among the hallmarks of cancer cells. Gene alterations can change the sequence or amount of mRNA and the resulting proteins that are produced, which in turn can contribute to cancer development (see Sidebar 7, p. 30). Genetic alterations can be inherited (called germline mutations) or acquired during a person’s lifetime (called somatic mutations). In about 10 percent of cancer cases, the mutations are inherited. Germline mutations occur in a body's reproductive cells (egg or sperm) that are passed on from parents to children and become incorporated into the DNA of every cell in the body of the offspring. These types of mutations can increase their risk of developing cancer, although not all germline mutations contribute to cancer development. Inherited genetic alterations that play a role in cancer development are among the pathogenic germline mutations (see Figure 5, p. 31). We are making great strides in understanding germline pathogenic mutations, thanks to advances in research and technology. As one example, a recent study utilizing cutting edge DNA sequencing found that 13 percent of patients with endometrial cancer had germline pathogenic mutations, and 63 percent of these mutations occurred in genes that are known to drive cancer development (69). These findings can help researchers identify new ways to test individuals and their family members for risk of developing endometrial cancer, as well as devise new strategies for minimizing the possibility of developing cancer. Somatic or acquired mutations occur over an individual’s lifetime due to errors arising during normal cell divisions or because of environmental exposures, lifestyle factors, and/ or health conditions. Research has revealed that tumors originating from different sites, as well as different tumor masses originating from a primary tumor within a person, contain different somatic mutations. For example, two recent studies evaluated metastatic tumors from different patients and from different sites within each patient to understand how metastatic lung cancer grows and spreads inside the body. Findings from these studies showed that genetic features of metastatic lung tumors from separate sites differed greatly within a patient and across patients and that these differences determined when and how the cancer would recur (70,71). Understanding the Path to Cancer Development AACR Cancer Progress Report 2023 29
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