The Impacts of Lung Cancer Genomics on Precision Medicine
In the past, one of the ways genomics aided in the medical field was by identifying rare diseases in newborns, such as Down syndrome and Turner syndrome.1 However, genomics and genetic testing are beginning to be applied to more common diseases such as cancer. Genetic testing can inform health care providers of existing genetic mutations which can improve risk prediction, prevention, diagnosis, and prognosis of a disease.2 Hereditary cancer risks may prompt some patients to choose to get surgeries due to the high likelihood of developing cancer. These patients that survive a predisposition to cancer are called cancer previvors.3
Currently, genomics is being used to assess the susceptibility of various races and ethnicities to lung cancer by analyzing the frequency of various mutated genes in those populations. Furthermore, with increased genetic material being analyzed, there may be higher chances of recovery due to the discovery of better treatments for people with specific genetic mutations. This form of medicine is known as precision medicine, which is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”4
There are a few notable somatic mutations, mutations that are not inherited, that contribute to lung cancer which include: the epidermal growth factor receptor (EGFR) gene mutation, the KRAS proto-oncogene mutation, and TP53 gene mutation.5 Cancers form when cells do not die and instead uncontrollably divide (proliferate). Mutations in these genes can cause increased cell division rates and inhibit apoptosis, programmed cell death, which can form a mass of cancerous cells called a tumor.
Cancers form when cells do not die and instead uncontrollably divide (proliferate)
At least eight mutations of the EGFR gene are known to be associated with non-small cell lung cancer. Lung cancer caused by a mutation of this gene is most common in non-smokers. The EGFR gene produces a protein called the epidermal growth factor receptor which is present in both healthy and cancer cells. In its normal function, EGFR can bind to at least seven different ligands, including epidermal growth factor (EGF), transforming growth factor α (TGFα), and amphiregulin (AREG), resulting in a series of signaling cascades inside of the cell, which cause cell proliferation.6 However, when the EGFR gene mutates, the receptor protein becomes activated even when it is not bound to a ligand.7 This activation results in continuous cell-reproduction and survival, forming abnormal cell tissue masses, resulting in lung cancer.
The KRAS proto-oncogene has at least three mutations that cause cancer. This gene codes for the K-RAS protein that converts guanosine triphosphate (GTP) molecules into guanosine diphosphate (GDP). When K-RAS is turned on through binding to a molecule of GTP, it relays signals from the outside of the cell to the cell’s nucleus which promote cell growth and division. However, when K-RAS binds to GDP, it no longer transmits signals from outside of the cell to the nucleus. When the KRAS gene is mutated, it causes amino acids in the K-RAS protein to be changed, resulting in the K-RAS protein being constantly activated. When this mutation occurs in the lungs, the lung cells will then uncontrollably proliferate which can lead to a lung tumor.8
The TP53 gene codes for p53, a tumor suppressor protein located in the nucleus of cells. It is essential for DNA reparation, as it activates genes to fix DNA damage. It also signals cells with damaged DNA to undergo apoptosis if the damage cannot be repaired. By fixing damaged DNA and preventing mutated cells from undergoing division, tumor protein p53 halts tumor formation. However, with a TP53 gene mutation, p53 does not function normally, and damaged DNA can accumulate. These mutations can lead to uncontrolled cell division, leading to tumor growth.8
Genomics Impact on Precision Medicine
It is imperative to understand how these mutations affect different populations in order to understand the health risks faced by each racial or ethnic group. China is in the midst of a lung cancer epidemic. Lung cancer is the leading cause of cancer mortality in China, accounting for 21.7% of cancer mortality and 610,000 deaths in 2015.9 In a 2019 study, for genomic and somatic alterations, EGFR mutation rates for the Chinese population were determined to be 39-59% while The Cancer Genome Atlas (TCGA) program determined a mutation rate of 14% for non-Hispanic Caucasians. Furthermore, the KRAS gene mutation was found to be higher in non-Hispanic Caucasian populations than Chinese populations (TCGA: 31% vs. Chinese: 7-11%). Furthermore, the TP53 gene mutation rate was 53% in non-Hispanic Caucasian populations, according to the TCGA, compared to 44% in the Chinese population.5
Understanding the different rates of the various genetic mutations across racial and ethnic groups is essential to understand the risk one has for developing lung cancer. Through genomic testing, doctors can observe if patients inherit any genetic mutations that put them at an increased risk for cancer. The use of accurate genetic tests and family health history can help physicians utilize precision medicine.2 An example of precision medicine in lung cancer treatment can be seen with the IRESSA (gefitinib) drug.
In the past, IRESSA was not FDA approved because clinical studies demonstrated no improvements in progression-free survival (PFS) among lung cancer patients in the populations they studied, which were mainly non-Hispanic Caucasian Americans. PFS is the time during and after the treatment of a disease that a patient lives with the disease, but it does not get worse.10 However, through the IRESSA Pan-Asia Study (IPASS), the use of IRESSA was shown to be superior to first-line chemotherapeutic drugs used for advanced non-small cell lung cancers in people of Asian descent, where the EGFR gene mutation is more common.11 In the few years where the drug was not FDA approved, many cancer patients’ lives may have been lost because they were unable to access IRESSA. With genomic advances, future research projects can account for the differences in mutations across various populations and conduct more precise studies, by ensuring that groups primarily affected by a specific genetic mutation are well-represented in the study. These thorough studies will assist in creating accurate results that benefit all populations and can pave the way for the future of precision medicine.
Modern and Future Application of Genomics in Cancer
The Memorial Sloan Kettering Cancer Center (MSK), widely regarded as one of the world’s best cancer hospitals, uses MSK-IMPACT, a targeted test for mutations in both rare and common cancers. The US Food and Drug Administration approved MSK-IMPACT in November 2017.12 This genomic test screens for over 300 genetic mutations at once and can be used on solid tumors such as lung cancer, as well as liquid tumors such as blood cancer.13 At the MSK cancer center, doctors and researchers have developed a precision oncology knowledge base called OncoKB. OncoKB provides the biological and clinical effects of over 4,000 genomic changes. This knowledge base gathers information from public databases, scientific literature, and clinical guidelines. This genomic information is accessible to both the public and physicians. OnkoKB can also support clinical decision-making as it suggests the best treatments for a tumor’s genomic profile.12
Disparities in treatment are often caused by a doctor’s implicit bias toward a race or ethnicity. In a 2010 study, Dr. Samuel Cykert found that doctors are less likely to recommend black patients with early-stage lung cancer for lung cancer surgery compared to white patients (66% vs. 55%).9 In the same study, Dr. Cykert found that black patients with two or more comorbid illnesses along with lung cancer only had a surgery rate of 13%.14 According to Dr. Cykert, “Doctors were less willing to take the same treatment risks with patients who were [racially] different from them.”14 However, with new technologies such as MSK-IMPACT that can objectively find mutated genes and suggest the most appropriate treatment, doctors should be less likely to follow their biases and more likely to follow the objective optimal treatment.
the goal of this genomics technology is to gather and share data within MSK and the public
For the future of MSK-IMPACT in precision medicine, the goal of this genomics technology is to gather and share data within MSK and the public. There have already been over 100 scientific publications by MSK authors who have used MSK-IMPACT testing results, with many more to come. With MSK partnering with other institutions through the American Association for Cancer Research consortium, additional tumor-sequencing data can be used to develop more efficient cancer therapies.12 Hopefully, in the future, more cancer treatment centers will adopt similar technology as it will allow for large pools of data-sharing. Data throughout the world can be compiled and used in cancer research studies, pushing the frontier for more optimal cancer treatments and efficient precision medicine therapies, which may save many lives.
I would like to thank ResearcHStart/Introduction to Cancer Research Program at the University of Illinois Cancer Center, Chicago, IL for sharing this opportunity and guiding me through the writing process.
About the Author
David is a senior at Naperville Central High School and participates in his school’s science olympiad, academic challenge, and varsity tennis team. In the future, he hopes to pursue a career in the field of medicine and public health, working worldwide to help people from various backgrounds.