Unity of Cancer Genetics Cancer is often described as a genetic disease, but a neglected aspect is that cancer is also a universal disease.

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1 Unity of Cancer Genetics Cancer is often described as a genetic disease, but a neglected aspect is that cancer is also a universal disease. Genetics is one of the factors of cancer that connects all people together everyone has DNA and everyone has the potential to suffer DNA damage. The NCI estimates that approximately 38.5 percent of people living in the United States will develop cancer at some point in their life (NCI Cancer of Any Site ). This means a significant percentage of the population will develop it in their lifetime and virtually the entirety of it will be affected some manner, e.g. have friends or family that develop cancer. The very basis of cancer is that cells mutate, in ways that inhibit regulation of division. So, to better understand cancer one must focus on two main topics, genetics and ubiquity. There are specific gene mutations that cause cancer known as oncogenes and tumor suppressor genes. An oncogene is defined as a mutated form of a normal cellular gene called a proto- oncogene that contributes to the development of a cancer. Proto-oncogenes typically regulate basic processes that direct cell growth and cell differentiation (Bunz). One aspect that makes these gene mutations different is that in an oncogene, they do not eliminate but instead alter the functions the proteins they encode. The activation of an oncogene is only part of the picture, the inactivation of tumor suppressor genes is also a huge contributing factor to tumor development. Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. In many tumors, these genes are lost or inactivated, thereby removing negative regulators of cell proliferation and contributing to the abnormal proliferation of tumor cells (Cooper). Mutations in these sort can be inherited or caused by external factors. These distinction between mutations are called germline and somatic mutations. Somatic mutations are mutations that arise after conception and can occur in any cell that is not a reproductive cell; therefore these mutations are not inheritable and cannot be passed on to children. Germline mutations, on the other hand, are mutations that occur in reproductive cells meaning they are heritable mutations. (Griffiths) A germline mutation can either be inherited from one s parents or induced spontaneously which could potential be passed off to one s offspring. Most cancer mutations are somatic, but there are instances where they are heritable. Examples of germline muttaoins can be found in many types of breast cancer and in Lynch syndrome. In breast cancer, many women whose mothers have had breast cancer are encouraged to undergo genetic testing for the BRCA mutations. In a family study conducted by the Breast Cancer Linkage Consortium, breast cancer was linked to BRCA1 in an estimated 52% of families and to BRCA2 in 32% of families showing that there is a strong linkage between the BRCA mutations and heritable breast cancer (Ford et al.). Genetic testing for these genes can be a powerful tool when planning treatment for women. After undergoing genetic testing, women who test positive are faced with a very difficult decision of a preventative double mastectomy or assuming the risk of getting breast cancer. From personal experience, I can tell you that this is not an easy situation in which to be. My mom s mother and sister have both had breast cancer, which required surgery, chemotherapy, and radiation. For years, my mom has refused to get the genetic testing because she felt that if she had either mutation, she would feel compelled to have a double mastectomy. I would not recommend this course of action to anyone as ignorance can be dangerous. Even if a person knows that they have a BRCA mutation it does not mean that they have to take drastic preventative measure and it allows them to be more alert and would encourage them to more aware of things such as lumps forming in the breast tissue.

2 Sarubbe 2 After a long time, my mom finally gave in to both my mine and my sister s lecturing and got the test done a few months ago, for which she was negative for both BRCA1 and BRCA 2. Another significant type of heritable cancer is Lynch syndrome. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is which is an uncommon genetic predisposition to develop certain cancers, predominately colon cancer. It is thought to mainly be caused by defects in the MSH2 and MLH1 genes which are responsible for DNA repair. Since defects in the MSH2 gene may account for as many as 60% of cases, and defects in the MLH1 gene may play a role in up to 30%, defects in these 2 genes likely account for the vast majority of cases (OMIM Entry). Lynch syndrome is a frightening genetic condition, which has a prolific impact on the lives of those that have it. These people have not only the personal physical struggles of dealing with their own cancer but also a lot of the psychological struggles of passing on such a terrible genetic disease onto their children. They watched many of their family members die from cancer and how some find out they had Lynch Syndrome because of this. Genetic testing for a condition like this is invaluable We are living with Lynch as a family and realize together we can get through anything. My physician told me that my cancer saved my children s lives. If I hadn t gotten cancer and the Lynch testing, my son may not have reported his rectal bleeding and he could have had an entirely different outcome (My Lynch Story). Causes of cancer are highly debated, and there is often a issue of whether cancer is predominately caused by random mutations caused by endogenous cell errors or by environmental factors. Some claim that up to 90-95% cases of cancer are due to environmental factors (Anand et al.). While it is a highly-debated topic, recent research may suggest that a significant portion of cancer-causing mutations are random and there is no easy way to prevent it (Nowak and Waclaw).While many cancers may be randomly induced, there are more certain things that are carcinogenic. These include cigarettes, weight, hormones, viruses, and radiation. Smoking is a major contributing factor to developing cancer. According to the CDC, smoking cigarettes accounts for about 80 to 90 percent of all lung cancer cases in the United States (CDC). Even nonsmokers, who are exposed to second-hand smoke have an increased risk of developing lung cancer. In a 2006 study on the effects of secondhand smoke, the Surgeon General claims that by simply living with a smoker the risk for developing lung cancer is increase by 20 to 30 percent for nonsmokers (Surgeon General). Weight is another major contributing factor to cancer. A group of researchers did a metaanalysis of 49 different papers and they looked at a number of different measures of body weight and compared them to the incidence and mortality of different cancers. In 31 out of the 35 significant meta-analyses conducted, they ultimately found an increase in body mass index was associated with a higher risk of developing esophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma (Kyrgiou et al.). While not entirely new results, this study further cements the idea that certain types of cancer can possibly be staved off with proper diet and exercise. However, this study makes it clear that this is only a positive association not a causality of cancer and that proper health and weight management is mainly a good secondary preventative strategy for cancer. Hormones are slightly less definitive in terms of causing cancer, numerous studies claim that hormones can increase risks of breast and prostate cancer (Key). However, others argue that these are simply correlations induced by other primary factors specifically obesity.

3 Sarubbe 3 Both DNA and RNA viruses have been shown to be capable of causing cancer in humans. Epstein-Barr virus, human papillomavirus, hepatitis B virus, and human herpes virus-8 are the four DNA viruses that are capable of causing the development of human cancers. Human T-lymphotropic virus type 1 and hepatitis C viruses are the two RNA viruses that contribute to human cancers. (Liao) Viruses may contribute to the development of human tumors by different mechanisms: indirectly by inducing immunosuppression or by modifying the host cell genome without persistence of viral DNA; directly by inducing oncoproteins or by altering the expression of host cell proteins at the site of viral DNA integration. Human cancers associated with papillomavirus, hepatitis B virus, Epstein-Barr virus, and human T-cell leukemia-lymphoma virus infections are responsible for approximately 15 percent of the worldwide cancer incidence. Cancer of the cervix and hepatocellular carcinoma account for about 80 percent of virus-linked cancers. (zur H) Endogenous cell errors may be another huge cause of cancer mutations. The rate at which cells divide plays a key role in causing these cell errors and this is supported but the notion that cancers arise more frequently in tissues that are highly proliferative meaning that the higher the cell turnover rate the higher the cancers of these types of cells becoming cancerous (Tomasetti and Vogelstein). I always found this to be a really intuitive way of understanding one of the reasons cancer happens. If you have more cells divisions, naturally you are going to have more spontaneous mutations and using the context of the article above, this accounts for almost 2/3 of certain cancer cases. When one smokes they force their lungs to repair, increasing the cell growth which leads to elevated risks of mutations and thus increases the chance of developing cancer. Innovative technologies are always being developed and used to target cancer on a genetic level. In a lecture, Olivier Elemento gave, he discussed the use of personalized medicine in cancer patients. To do this, they sequence the DNA and RNA of tumor cells of different time frames and identify the different types of mutations present. After identifying the mutations, they sort the mutations based on if they are deemed to be the driver (cancer-causing) or passenger (innocuous) mutations and then cross-reference this with a database. They then determine if any of these mutations can be treated with available medicine that specifically targets the identified mutations. An example Olivier gave was female bladder cancer patient who they found had an unusual mutation for bladder cancer patients usually seen in breast cancer, HER2. This mutation is treatable and they were able to drive the woman s cancer into remission. Another aspect of precision he touched upon was that in his lab they could take live tumor cells to perform multiple drug screenings on to determine which drug would combat the tumor. His lab also developed a heuristic based on a very small to determine if patients would respond to immunotherapy, which was largely based on the amount and variety of T-cells and if the cancer cells had passenger mutations which could easily be recognized by the immune system. (Elemento) Current advancements are also being made in regard to CRISPR/Cas 9. CRISPR is a method of genomic editing that works in a complicated way and goes well over my head. But the big picture is that CRISPR/Cas9 is drastically changing the field of molecular biology by making gene editing affordable and accessible. Recently, scientists in Germany found that they could remove cancer mutations without affecting healthy cells using this method of gene editing (Gebler et al.). It is definite a step in the right direction, but it is by no means a cure-all. The article then went on to explain that each cancer shows a specific combination of many mutations, therefore the treatment would be very different depend on the type of cancer. More

4 Sarubbe 4 research also needs to be done at this point to identify these mutations, as well as testing of the CRISPR/Cas9 process in humans. Cancer research and treatments are becoming increasingly specialized and focused on the genetic aspects of cancer. This understanding of the basics of cancer genetics is critical in treating the disease and evaluating how cancer matters in an individual context. While there are controllable aspects of cancer, a large component is spontaneous mutation; these are not preventable and have the potential to affect everyone. This makes cancer a universal phenomenon and necessitates a united front to combat it. Works Cited Anand, Preetha et al. Cancer Is a Preventable Disease That Requires Major Lifestyle Changes. Pharmaceutical Research 25.9 (2008): PubMed Central. Web. Bunz, Fred. Principles of Cancer Genetics. Dordrecht: Springer Netherlands, CrossRef. Web. 10 Apr Cancer of Any Site - Cancer Stat Facts. NCI. N.p., n.d. Web. 16 Apr CDC - What Are the Risk Factors for Lung Cancer? N.p., n.d. Web. 10 Apr Cooper, Geoffrey M. Oncogenes. 2nd ed. Boston: Jones and Bartlett Publishers, Print. The Jones and Bartlett Series in Biology The Cell: A Molecular Approach. 2. ed. Washington, DC: ASM Press [u.a.], Gemeinsamer Bibliotheksverbund ISBN. Web. 16 Apr Cowell, John K. Molecular Genetics of Cancer. Oxford; San Diego, CA: Bios ; Distributed by Academic Press, Print. Elemento, Olivier. Immunogenomics and Single-Cell Omics for Cancer Precision Medicine. Weill Hall, Ford, D et al. Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families. The Breast Cancer Linkage Consortium. American Journal of Human Genetics 62.3 (1998): Print. Gebler, Christina et al. Inactivation of Cancer Mutations Utilizing CRISPR/Cas9. Journal of the National Cancer Institute (2017): djw183. CrossRef. Web. Genetics. cgvarticle. National Cancer Institute. N.p., n.d. Web. 10 Apr Griffiths, Anthony J. F., ed. An Introduction to Genetic Analysis. 7th ed. New York: W.H. Freeman, Print. Kelly, Victoria R. et al. Long-Term Sodium Chloride Retention in a Rural Watershed: Legacy Effects of Road Salt on Streamwater Concentration. Environmental Science & Technology 42.2 (2008): CrossRef. Web. Key, T. J. Hormones and Cancer in Humans. Mutation Research (1995): Print. Kyrgiou, Maria et al. Adiposity and Cancer at Major Anatomical Sites: Umbrella Review of the Literature. BMJ 356 (2017): j Web.

5 Sarubbe 5 Liao, John B. Viruses and Human Cancer. The Yale Journal of Biology and Medicine (2006): Print. M. D. The Health Consequences of Smoking-50 Years of Progress. A Report of the Surgeon General, US Departement of health and human services. Office of the Surg. Gen., Atlanta US (2014): 944. Print. My Lynch Story Is Rare and Unique. Lynch Syndrome International. N.p., n.d. Web. 13 Apr Nowak, Martin A., and Bartlomiej Waclaw. Genes, Environment, and bad Luck. Science (2017): science.sciencemag.org.proxy.library.cornell.edu. Web. OMIM Entry - # LYNCH SYNDROME. Online Mendelian Inheritance in Man. N.p., n.d. Web. 13 Apr Tomasetti, Cristian, and Bert Vogelstein. Variation in Cancer Risk among Tissues Can Be Explained by the Number of Stem Cell Divisions. Science (2015): science.sciencemag.org.proxy.library.cornell.edu. Web. United States, ed. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Rockville, MD: U.S. Dept. of Health and Human Services, Public Health Service, Office of the Surgeon General, Print. zur Hausen, H. Viruses in Human Cancers. Science (New York, N.Y.) (1991): Print.