Srivarchala+Chandu 

I. Cancer
Ana grew up in a small village with her parents, three siblings, and an extensive family. When she was 20, she got married to a businessman who lived in her village. A few years later they moved to the city to keep their small business running. Less than 15 years later, business is booming, and Ana is now a 32 year old mother of 5 who recently gave birth to a baby girl. She has been experiencing vomiting and headaches. In addition, she has been dealing with headaches, and mood swings. She does not discuss her symptoms with her husband, and worries constantly about her young children. One afternoon when Ana was at home with her children she had a seizure. Her husband and kids were playing outside, and when they had come back in to get some water, they saw their mom on the floor. Her husband immediately called the ambulance and met her at the hospital where the doctor had many concerns about Ana’s recent health issues. They then went on to do an MRI and unfortunately for Ana the diagnosis was a brain tumor. After a biopsy, she was given the diagnosis of a grade 3 astrocytoma, or cancer of an astrocyte, also known as Anaplastic Astrocytoma. An astrocyte is a glial cell, in the brain, that supply the neuron with nutrients and support the endothelial cells at the blood-brain barrier. ======Hurty, Arne. The Other Brain Cells. Stanford Medicine. By Bruce Goldman. Web.======

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Most cases of Anaplastic Astrocytoma progress from a smaller tumor, grades 1 or 2, and may further grow into a grade four tumor. The grades of a tumor are increasingly worse, so the higher the grade the larger or more aggressive the tumor. Ana did not show common signs of diseases that precede developing astrocytomas, including “neurofibromatosis types 1 and 2, tuberous sclerosis, and Li-Fraumeni syndrome”. But after genetic testing of her tumor, the doctor told Ana that she shows a loss of heterozygosity, on chromosome 19. This means that Ana has lost part of a gene on one of her chromosomes. While Ana’s is an isolated case, meaning that members of her family do not have this type of tumor, there is a very high chance of genetic predispositions to this disease. The standardized incidence ratio (SIR) is a statistical value that indicates the ratio of people who have a tumor to people who were supposed to have the same tumor. The “SIR was doubled for astrocytoma when parents were diagnosed with astrocytoma”, meaning if Ana’s parents had a Anaplastic Astrocytoma then she would be twice as likely to get it, than someone whose parents did not have Ana plastic Astrocytoma. While among siblings this ratio was tripled indicating a higher chance of Anaplastic Astrocytoma, if Ana’s siblings were to have the same condition. This also means that Ana’s children, and siblings will have to be tested for astrocytomas. In Ana’s case, this type of brain tumor is considered cancerous and does not have very high survival rates. About 25% of people who get diagnosed with this cancer will survive the first five years after daignosis. Anaplastic Astrocytoma is very aggressive and if it continues to develop it will grow into a larger tumor. Anaplastic Astrocytoma growth varies by person, and can only be tested by multiple MRI or CT scans over a period of time. Unlike other cancers, Anaplastic Astrocytomas “do not metastasize, and move to different parts of the brain and body, rather they are usually localized in the brain”.

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Unfortunately, the prognosis for this disease is dependent on where the tumor is located, and the age of the patient. Ana is 32 and her tumor is located her parietal lobe. The long term prognosis is that most patients will experience reemergence of the disease and will die from cancer. For Ana, this means that while she may have a strong chance of survival because, her tumor is in the parietal lobe of the brain and will eventually affect her sensation, perception and spatial perception, if it is left untreated. =====

II. Molecular Markers
In order to fully understand what makes this cancer different from others, and how we can eventually treat it, we must look at its molecular basis. After her biopsy, Ana's doctors have found that she has multiple mutations. In general, Anaplastic Astrocytomas, tend to show mutations in four major genes: //TP53, IDH1/2//, //ATRX// and //MGMT//. Another major mutation that Ana has is a deletion in one arm of chromosome 19. Each of these genes have a specific function and when mutated lead to cancer. First, we can look at the //TP53// gene, which codes for the p53 protein. p53 is a transcription factor that is also a tumor suppressor and halts the development of tumors that may lead to cancer. It is activated by damage in the cell, and allows the cell to repair itself or kill itself

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Ryan, Kevin M., Andrew C. Phillips, and Karen H. Vousden. "Regulation and function of the p53 tumor suppressor protein." Current opinion in cell biology 13.3 (2001): 332-337. . . Most of the mutations in this protein are located where the protein binds DNA. This signals to us that the binding of p53 to DNA is important. p53 has many substrates, or effectors, that can tell us more about how its function can be affected in a way that leads to cancer. Figure 3 also shows us that p53 responds to cellular stress or DNA damage during the cell cycle. In this case, p53 can lead to apoptosis, cell death, or halt the cell cycle so that the cell can repair itself. In order to lead the cell to apoptosis p53 induces the transcription of proteins that lead to two different apoptotic pathways, the mitochondrial apoptotic pathway and the death receptors pathway. For our purposes we will only focus on the mitochondrial apoptotic pathway. If we go back to Figure 3, we can see that p53 starts a pathway that leads to the expression of proteins like BAX. BAX then triggers the mitochondria to release cytochrome c which activates the protein complex, Apaf-1/caspase-9 apoptosome. This protein complex leads to apoptosis, or cell death. So, then, if this protein is mutated it can lead to cancer, because p53 respond to DNA damage and stressors that are telling the cell that it needs to kill itself. But p53 and its functions are not only affected by direct mutations to p53, but also to its substrates. For example, p21Waf1/Cip1, is a direct p53 target and a change to this protein diminishes its response to p53. So even though //TP53// is not mutated the p53 protein cannot perform its function fully because its substrate is mutated, and does not respond to p53. This pathway is important because it allows our cells to kill themselves if it cannot be repaired. Without the use of this pathway, cells can contiue to grow even though they are dangerous to the body because they lack certain functions. // IDH1/2 // codes for two proteins called isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2) which are involved in the citric acid cycle. As Figure 4 shows us, IDH proteins use NADP, to remove a carbon from isocitrate and form α-ketoglutarate, this process produces NADPH. In Ana's cancer IDH1 and IDH2 proteins are the ones that are mutated. These proteins share a high degree of sequence similarity (70% in humans), so they are genetically very similar. The difference between them is where they are located. IDH1 is located in the cytosol of the cell, while IDH2 is located in the mitochondria. IDH1 and IDH2 both play “important roles in a number of cellular functions." IDH1 has specifically been shown to play a critical role in lipid metabolism by promotes lipogenesis, or the creation of new lipids under stress conditions . The most important function of IDH1 is that it is the principal source of NADPH, an energy molecule, in the human brain. This makes this protein specifically important to our cancer. A lterations of these proteins impairs their normal ability of IDH1/2 to convert isocitrate to α-ketoglutarate (αKG) and instead they convert αKG to D-2-hydroxyglutarate (2HG) .This increase in 2HG has shown to increase the levels of methylation and epigenetic changes to the cell's DNA . These epigenetic changes will then lead to more changes in the way that the DNA is read and eventually what proteins are made.  Our next gene is //ATRX//, which codes for a protein ATRX. When mutated this protein is involved in telomere lengthening. This is important because teleomeres, repeating sequences at the end of chromosomes, are shortened at the end of every replication cycle. So as the cancer cells grow and divide their telomeres get shorter, which means that their genetic information will eventually be damaged beyond repair. This will cause the cancer to grow and leads to more mutations. We see this in Ana’s case as her cancer cells have a loss of heterozygosity on chromosome 19. This means that her cells have lost an entire gene. With the mutation of ATRX there will be a lengthening of these telomeres, and so there will be replicative immortality, another hallmark of cancer. Replicative immortality is important because it means that the cell is able to grow and divide forever. While, the deletion in the chromosome 19 arm has not yet been linked to a protein, its presence has been statistically linked to different prognosis. Patients with this deletion, like Ana, will have a higher rate of reoccurrence, and leads to the cancer being more agressive. Lastly, //MGMT// codes for a protein that is a transfer methylase, and is involved in repairing alkylating damage, like the damage that is caused by certain chemotherapies. Because this protein is involved in repairing damage that is done by chemotherapy, patients with a mutation in this protein will be more sensitive to chemotherapy. In Ana's case, her cancer has a methylated promoter that inactivates the MGMT protein. Research has found patients have a better prognosis because the tumor cells are not able to repair themselves.

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All of the genes that have been mutated are important to the growth and initiation of Ana’s cancer. These mutations have shown us that the functions of these proteins are extremely important to how Ana should be treated. =====

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After her diagnosis Ana is now in the hospital accompanied by her husband. She is worried about her kids, and scared that they will grow up without a mother just as she did. Her doctors come to visit her and go over the various options that she has based on her diagnosis. Surprised to hear she has a choice in her treatment, she is grateful for the information that the doctors have provided. ===== Astrocytomas are difficult to treat because they have an irregular shape, as the cells themselves are star-shaped (Figure 1). This means that while her tumor is operable and can be treated through surgery, her doctors recommend her to do both adjuvant treatment as well as a surgical resection of the tumor. This will allow the doctors to target her tumor specifically, and thoroughly. As we discussed in the previous section, the molecular basis for this particular cancer relies on its ability to deregulate the p53 protein that stops abnormal growth of cells. This means that even though the cancer is “gone” there will be a chance that it comes back if the entire tumor and all cancerous cells are not taken out. This is where adjuvant treatment can help. Adjuvant treatment is given after the primary treatment of surgery. This is important because the initial resection may not get the entire tumor, so the adjuvant treatment will, hopefully, get rid of the rest of the cancerous cells. The doctors also discussed with Ana the option of participating in a clinical trial. Clinical trials are a great way for oncologists and researchers to learn the potency of the drug as well as how to further tailor the drug to certain treatments, to be most effective. Ana is concerned with the side effects of chemotherapies, as she has previously seen some of her friends suffering. Her doctors reassure her though that chemotherapies are used for recurrent and aggressive tumors. Another option may be systemic drugs that affect the entire body, and while Ana’s cancer has not metastasized, or spread throughout her body there might still be need for this type of chemotherapy. Systemic drugs must also pass through the blood-brain barrier, which is a barrier that protects the brain from neurotoxins.

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Ana then would receive radiation as her adjuvant therapy. Radiation therapy is the use of highly concentrated radiation, like x rays, to kill cancer cells. This is helpful because it concentrates the radiation to a specific part of the body. But its side effects include fatigue, and a risk of developing another cancer. ===== The clinical trial that Ana could be a part of, combines a drug called, temozolomide with radiation therapy

temozolomide chemotherapy in patients with malignant glioma]." Zhonghua yi xue za zhi 95.31 (2015): 2522-2525. .
. Temozolomide is an alkylating drug that damages the DNA at certain locations, like guanine residues, which triggers cell death =====Zhang, W., et al. "[Randomized controlled study of limited margins IMRT and=====

temozolomide chemotherapy in patients with malignant glioma]." Zhonghua yi xue za zhi 95.31 (2015): 2522-2525. .
. As discussed in the previous section, Ana has an epigenetic mutation in her MGMT protein. This means that she will be more sensitive to the temozolomide treatment =====Zhang, W., et al. "[Randomized controlled study of limited margins IMRT and=====

temozolomide chemotherapy in patients with malignant glioma]." Zhonghua yi xue za zhi 95.31 (2015): 2522-2525. .
. This trial would allow doctors to test the effectiveness of the drug in combination with radiation therapy. This clinical trail would be randomized, so Ana might or might not receive the drug. This allows the study to get rid of biases that the doctors may have in giving some patients the medication. It also gets rid of placebo effect, and makes sure that the drug is actually doing what it is supposed to. There are side effects to this treatment, as it combines two different types of therapies that might hurt Ana more than they help her.

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Ana decided to signup for the clinical trial, but first she needed to get her resection surgery. While sitting in the ward she sees many people around her with similar brain tumors, and while she feels a sense of community, she sees that many are dying and new patients are coming in everyday. Her initial fear and stress return. But she is soon taken into get her cancer resected. The surgery goes well and when the pathology reports come back about her cancer, her doctors see that there are clean margins. This means that they have gotten the entire tumor and there is no cancer in the surrounding tissue. Unfortunately for Ana she cannot move her right arm, and has limited vision in her right eye. Her doctors tell her that she will need physical therapy. They are also worried about her ability to handle chemotherapy along with radiation. They believe that her quality of life will become more compromised, and want her to first recover from her surgery. But this also means that she cannot go through with the clinical trial. Her doctors reassure her that the drug will not help Ana as her tumor appears to have full been resected. But she will need to come back monthly for checkups, to make sure there is no recurrence. =====

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Fortunately for Ana she is able to regaining control of her arm and even her vision is slowly improving. Her cancer has not yet returned, but she is vigilant and goes to yearly checkups, frightful that the cancer will return. For now, she can take care of her children and is thankful for her life. ===== Apercu:

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Brain Tumors do not discriminate. They affect people of all ages and only 34 percent of people who have brain tumors will survive for 5 years after their initial diagnosis. This is a daunting statistic, but as treatments and diagnosis gets better there is hope for people with this deadly disease. ======