NRS-410V GCU Topic 2 Nursing Questions

NRS-410V Lecture 2 Genetic Alterations and Cancer Introduction Congenital disorders or birth defects and many common diseases such as cancer are directly related to alterations in the genetic structure of deoxyribonucleic acid (DNA). A general knowledge of the principles of inheritance, the cell cycle, and the impact environmental influences have on the genetic structure are crucial to understanding the disease processes, ongoing research, and current disease treatments. Aberrant Chromosomal Numbers Congenital disorders or birth defects are more common than we realize. Many spontaneous abortions are due to chromosomal defects, whether it is the number of chromosomes or the construction of the chromosomes. Down syndrome, or trisomy of chromosome 21 (three copies instead of two), is the most common chromosomal disorder that occurs during meiosis (Porth, 2007). Aberrant Chromosomal Structure During the process of meiosis, chromosomes often exchange blocks of DNA or alleles, causing variation in the chromosomes. When the exchange is not precise, the alterations may prove fatal to the gamete. This exchange of chromosomal material can also occur during mitosis and the cell may die or the mutation may continue in the cell line. This translocation of genetic material is implicated as the cause of many cancers. One example is the Philadelphia chromosome, in which the translocation of DNA between chromosome 9 and chromosome 22 causes chronic myeloid leukemia (CML). The translocation results in a novel protein, tyrosine kinase that promotes

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unregulated growth of myeloid cells. A drug being used to treat CML, Gleevec (Novartis), specifically blocks this tyrosine kinase, slowing the growth of the myeloid cells (McCance & Heuther, 2006). Neuroblastoma is associated with duplication of the MYCN gene. This MYCN gene is an oncogene, meaning that in its nonmutated state, it directs and controls the proliferation of certain cells. In its mutated state, proliferation is uncontrolled, which leads to tumors. Single Gene Mutations During mitosis and meiosis, the chromosomes are copied exactly. If one or more of the base pairs in the DNA sequence of a gene is altered, there is the possibility of a point mutation in that gene. This single defective gene on one chromosome may cause serious alterations in the functioning of the body, such as Marfan’s syndrome. This is an autosomal dominant gene and has a 50% chance of being transmitted to offspring. The BRCA1 and BRCA2 genes are autosomal dominant and are linked with breast cancer. The BRCA1 is found on chromosome 17, while the BRCA2 is found on chromosome 13. The HER-2/neuis also implicated in breast cancer. With overexpression, this gene causes excessive growth signals to the nucleus. The drug trastuzumab (Herceptin), a monoclonal antibody, is used to treat women who have the HER-2/neu alteration because it blocks the receptors for growth factor. Mutations of the ras gene family prevents the breakdown of GTP, which then allows the cytoplasmic signaling molecules to remain active and stimulate cell growth inappropriately. Lung cancer, leukemia, colon cancer, and ovarian cancer are all linked to the ras gene (Copstead & Banasik, 2005). The p53 gene or tumor suppressor gene is responsible for apoptosis–or programmed cell death–and the repair of damaged DNA. This gene helps maintain the appropriate number of cells within tissues. A mutation of this gene allows the cells with damaged DNA to live and become more aggressive. Many breast cancers have one or all of these mutations, plus a few more. The p53 gene mutation is also linked to colon cancer and lung cancer. Autosomal recessive diseases require both copies of the gene to be defective. Cystic fibrosis and phenylketonuria (PKU) are prime examples of autosomal recessive genes. These disorders relate to enzymes that are incorrectly made rather than run-away cell growth. Punett squares and pedigree charts demonstrate the inheritance patterns of either recessive or dominant genes. Genetics and Common Diseases Heart disease, hypertension, diabetes, and many psychiatric disorders have a familial tendency which is linked to genetics. In coronary heart disease, lipids are highly involved in the formation of atherosclerotic plaques. Twenty or more genes have been identified that play key roles in lipid formation, transport, coagulation, and hypertension (McCance & Heuther, 2006). An angiotensinogen gene has been implicated as a cause for hypertension and preeclampsia. These altered genes along with other environmental and lifestyle risk factors increase the likelihood of developing the disease. In type I diabetics, the HLA-DR3 and/or HLA-DR4 allele have been identified. Alterations of genes around the insulin gene on chromosome 11 also increase the risk of developing type I diabetes (McCance & Heuther, 2006). For type 2 diabetes, several genes have been identified that may increase the susceptibility. One gene is involved in adipocyte differentiation and glucose metabolism, while mutation of the glucokinase gene alters glucose conversion in the pancreas. Environmental and Lifestyle Risk Factors Environmental Risk Factors With billions and billions of cells replicating, it is amazing that the process does not incur more errors. Environmental influences increase the risk of errors in replication. Known chemical carcinogens include benzopyrene, which is found in foods fried in fat. Nitrosamines found in smoked, salted, and cured foods are also powerful carcinogens. The tars and nicotines in cigarettes are also cancer promoters. In addition, the ultraviolet (UV) rays of the sun can cause mutation of the p53 gene, thereby causing squamous cell carcinoma and a mutation in the p16 gene related to melanoma. The UV light also activates tumor necrosis factor-α (TNF-α), which seems to reduce the immune surveillance system (McCance & Heuther, 2006). Lifestyle Risk Factors Obesity has been linked to increasing the risk of cancer. The adipose tissue produces enzymes that increase the levels of free estradiol and testosterone. The receptors react to the increased levels by causing cellular proliferation and inhibiting apoptosis (McCance & Huether, 2006), increasing the risk of tumor development. Viruses such as human papillomavirus (HPV), hepatitis B virus, and the Epstein-Barr virus have been associated with cancer. The DNA of HPV becomes integrated into the nucleus of cervical cells and directs the proliferation of the virus. Cell Cycle Now that the chromosomal and gene mutations have been discussed, the process of cell division and growth as it relates to cancer needs to be understood. Cells that replicate have a five-phase cell cycle. During the S phase of the cell cycle, chromosomes are replicated. It is during this phase that environmental factors can affect the exact replication and cause mutations. The end of the G2 phase allows for a quality control check of the replication. Alterations of the kinases that control this checkpoint allow mutations to continue rather than be corrected, increasing the chances of cancer. Chemotherapy agents have been developed that act on different phases of the cell cycle with the intent of blocking the replication of the cancerous cell along with normal cells. Methotrexate, an antimetabolite, enters the cell and inhibits DNA synthesis. Cyclophosphamide, an alkylating agent, causes the DNA strands to cross-link, preventing normal use of the DNA, as well as its replication. Tamoxifen blocks the estrogen receptor cells–preventing DNA synthesis–and the cells remain in the G0 or G1 phase rather than replicating. Tumor Cell Transformation Promotion Stage Once a cell has survived one gene alteration, it must be able to continue to replicate and survive. Promotion is the stage in which the altered cells proliferate. In the progression stage, cancer cells often lose their ability to function and are not like the original tissue cells. These cells are considered anaplastic. Contact inhibition is lost and the cancer cells overwhelm the area in which they began. These malignant cells secrete proteases that destroy healthy cells and allow space for the cancerous cells to grow. Cancer Cell Growth Continued growth of the cancer cells depends on an adequate blood supply. Tumor cells can secrete vascular endothelial growth factor (VEGF) along with other growth factors that promote angiogenesis. As the blood supply increases to the tumor, the metastatic potential increases. Research is directed toward developing agents that can block the enzymes that support angiogenesis. Without a good blood supply, cancer cells die. Cancer Expansion Cancer cells do not adhere to each other as do the cells in normal tissue. Given a good blood supply or a lymphatic channel, the cancer cells can break away from the primary site and metastasize to other areas in the body. It may take years for the cancer cells to overcome the normal cells in the new site, so they can go undetected. Cancer Signs and Symptoms Early Stages In the early stages of cancer, there are usually not noticeable symptoms. Fatigue-like pain is very subjective and the reason for the fatigue is being researched. Pain is due to inflammation, stretching of visceral surfaces, compression of nerve endings, and bone metastasis. In addition, pain control is an ongoing problem in treating patients with cancer. Later Stages Cachexia or severe malnutrition is found in the later stages of cancer and is often the cause of death. TNF-α produced by macrophages has been implicated as a cause for the depression of protein synthesis and the increase in protein degradation. Anemia is also a common finding, as are leucopenia and thrombocytopenia due to suppression of the bone marrow. Cancer Therapy Research Throughout the lecture, different treatment therapies have been mentioned. Surgery, chemotherapy, and radiation continue as mainstay treatments. Immunomodulation therapy uses interferons, interleukins, monoclonal antibodies, and hematopoietic growth factors to destroy cancer cells. The interferons inhibit cancer cell proliferation and stimulate NK cells, T cells, and macrophages. Interleukin 2 stimulates the proliferation of T cells, NK cells, and macrophages, increasing the number available to destroy cancer cells. Monoclonal antibodies are specific to certain tumor cell receptors blocking growth factors as well as identifying the cell to the NK cells as foreign. The hematopoietic growth factors are used to stimulate production of neutrophils, macrophages, erythrocytes, and platelets in order to support the tissues during the tumor destruction. Research into gene therapy involves attempting to alter the genetic structure of the tumor cells, making them more susceptible to the immune system, or replacing the missing p53 gene by transporting it into the tumor cell using an inactivated virus. Stem cell transplant involves harvesting stem cells from the bone marrow of a closely matched donor and transplanting the stem cells. The therapy serves to restore the function of the once cancerous bone marrow. In addition, research is being done on vaccines for specific cancers. The HPV vaccine, Gardisil, is a beginning, whereas another area of research is being studied to inhibit the protelytic enzymes that allow the cancer cells to expand and metastasize. Conclusion Understanding genetics is important for the clinician who works with families who are or wish to become pregnant in order to explain the risks of birth defects and other genetically linked diseases. Every nurse needs to be able to educate patients on the environmental and lifestyle risks associated with cancer along with the genetic link. For those patients who are already being treated for cancer, the nurse should be able to explain how the medications and radiation help treat the disease. References Copstead, L. E., & Banasik, J. L. (2005). Pathophysiology (3rd ed.). St. Louis, MO: Saunders Elsevier. McCance, K. L., & Huether, S. E. (2006). Pathophysiology: The biological basis fordisease in adults and children (5th ed.). St. Louis, MO: Mosby Elsevier. Porth, C. M. (2007). Essentials of pathophysiology: Concepts of altered health states (2nd ed.). Philadelphia, PA: Lippincott Williams & Wilkins. © 2013. Grand Canyon University. All Rights Reserved.
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