How DNA Revolutionized Oncology Care

Simply put: genetics is the study of a single gene; genomics is the study of all of the genes in an organism. Cancer begins when genes in a cell become abnormal and the cell starts to grow and divide out of control. 

Understanding Gene Mutations

Deleterious or pathogenic mutations are defined as abnormal changes in the DNA bases of a gene. The sequence, or arrangement, of the bases determines the gene and its function. Even a change in just one base among the thousands of bases that make up a gene can have a major effect. Mutations may stop a protein from being made or render it unable to function. Harmless mutations are called polymorphisms, but cells become malignant largely because of harmful, pathogenic mutations in their genes.

Typically, many mutations must happen before a cell becomes a cancer cell. The mutations may affect different genes that control cell growth and division. Mutations in tumor-suppressor genes stop them from recognizing and attacking malignant cells before they develop into tumors. Mutations may also cause some normal genes to become cancer-causing genes, known as oncogenes. Humans have two copies of each gene—one from each parent—and for a gene to stop working completely and potentially lead to cancer, both copies have to be damaged with mutations.

Inherited Versus Acquired Gene Mutations

An inherited gene mutation is present in the egg or sperm that formed the child. During fertilization, a zygote is formed. Because all the cells in the body come from the zygote, a mutation in the zygote is present in every cell in the body and can be passed on to the next generation. This is known as a germline mutation.

An acquired, somatic mutation is one not present in the zygote. Rather, it’s acquired some time later in life. It occurs in one cell and then is passed on to any new cells that are the offspring of that cell. This kind of mutation is not present in the egg or sperm that formed the fetus, so it cannot be passed on to the next generation. Acquired mutations are much more common than inherited germline mutations.

How Are Discoveries in DNA Changing Oncology Care?

The discoveries in DNA research and understanding have helped explain how cancer develops. The identification of predisposition germline mutations (https://www.cancer.gov/about-cancer/causes-prevention/genetics/genetic-testing-fact-sheet) affords the opportunity to identify individuals and families at increased risk for developing malignancies, allowing them to make good decisions about cancer prevention and early detection. This includes the well-known BRCA1/2 genes and those associated with Lynch syndrome, as well as the lesser-known genes for which testing is available.

Now, it’s also possible to analyze and sequence the DNA in a tumor (https://www.cancer.gov/about-cancer/treatment/types/precision-medicine/tumor-dna-sequencing) to identify genetic changes in cancer cells that may be driving the growth of an individual’s cancer. This information may help identify which therapies could be most effective against a particular tumor. Specific therapies can be selected based on the genetic make-up of the tumor.

Tumor testing is also used in breast cancer to predict risk of recurrence as part of the decision-making process to determine whether chemotherapy is indicated. This is done by examining a panel of single nucleotide polymorphisms (SNPs). Each SNP represents a difference in a single DNA building block, called a nucleotide. The combination of SNPs detected in the tumor can be used to predict recurrence. The higher the recurrence score, the more beneficial chemotherapy and other systemic therapy are likely to be.

What About Pharmacogenomics?

Oncology care is also seeing change through the science of pharmacogenomics (https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics). Pharmacogenomics—the study of the interaction between the genome and clinical drug response—evaluates the associations between drug efficacy, toxicity, and variation in drug metabolizing enzymes, receptors, transporters, and drug targets. The main priority of pharmacogenomics is to optimize treatment by understanding the underlying biological mechanisms and utilizing genomic contributions to treatment response to predict and individualize therapy and improve treatment outcomes.

For example, 5-fluorouracil (5-FU) metabolism is driven by dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene. It is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5-FU and the oral 5-FU capecitabine. True deficiency of DPD affects approximately 5% of the overall population (https://www.sciencedirect.com/topics/medicine-and-dentistry/dihydropyrimidine-dehydrogenase-deficiency). In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity. Understanding whether a patient has DPD deficiency allows providers to select an effective therapy with the least toxicity.

Celebrate National DNA Day

For National DNA Day, history buffs might also enjoy this engaging interview (https://www.youtube.com/watch?v=TYRrXO_22No) with James Watson and Francis Crick about the initial discovery of DNA. In honor of the 15th anniversary of the Human Genome Project, the National Institutes of Health’s National Human Genome Research Institute has an engaging list of 15 ways (https://www.genome.gov/27570876/15-for-15-celebration/) genomics is revolutionizing health care. Many other amazing resources (http://learn.genetics.utah.edu/content/basics/) are available to help explain genetic concepts in understandable terms.

The knowledge of how DNA works in human beings is revolutionizing cancer care by allowing providers to identify people and families at increased risk for developing malignancy, leading them to make good decisions about prevention and detection and enabling the most effective therapies with the least toxicity based on genetic profiling. For me, that’s a great reason to celebrate National DNA Day.