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1 Exam 2009-10-29 Molecular Oncology and Biostatistics Biomedicine program, T5 Name:________________________ Code:__________________________ Good luck! 2 Exam 2009-10-29 Molecular Oncology and Biostatistics Biomedicine program, T5 Writing hours: 10.00-15.00 Code:________________________ Grading: Basic questions Maxpoints: 50p. To get an E-A grade at least 30p are required. Advanced questions Maxpoints: 51p (F≤30, E:31-34, D:35-38, C:39-42, B:43-46, A≥47) 3 Good luck! 1. Explain the following tumor biological terms: (4p) a) Oncogene b) Restriction point c) Tumor progression d) Tumor angiogenesis 2. Explain the following clinical oncology terms: (4p) a) Brachytherapy b) Neo adjuvant treatment c) Tumor grade d) Tumor stage 4 3. Cancer development is commonly associated with changes in tumor suppressor genes (TSGs). Please describe three conceptually different ways in which TSGs are altered in tumor, and also describe how these three different types of alterations can be detected at the molecular level (4.5p) 5 4. A 59-year-old man who underwent a colonoscopy was found to have a tumor that proves on biopsy to be moderately differentiated adenocarcinoma. a) Please describe under what circumstances this patient would be likely to receive adjuvant therapy, and explain briefly why some colon cancer patients are recommended adjuvant treatment and others not (4p) b) Unfortunately the patient got a relapse of his disease a year later. In this setting targeted therapies against tyrosine-kinase receptors may be beneficial. Drugs targeting tyrosine kinase receptor in cancer have three principally different mechanisms of action. Please describe those mechanisms. (3p) 6 c) The response to therapy targeting tyrosine kinase receptors in colorectal cancer can today partially be predicted using molecular analysis of the tumor cells. Please give an example of such an analysis and also give a plausible explanation of why you think that the result of the analysis may predict the outcome of the treatment. (2p) 5. A patient with breast cancer turns out to have metastasis in the left lung as well as in the skeleton (in the breast bone, sternum). Please reflect upon why this patient may have developed metastasis specifically at these locations. (4.5p) 7 6. Approximately 10% of all cancer patients have a clear hereditary cause for their cancer. In colorectal cancer one gene causing hereditary cancer is the APC gene. a) Please describe the clinical picture in patients inheriting a mutant APC gene. (2p) b) Please describe briefly the normal molecular function of the APC-protein. (5p) 8 c) Please describe and reflect upon two ethical issues that may occur in the handling of patients with hereditary cancer. (2p) 7. Cancer immunotherapy has mainly been successful using monoclonal antibodies such as rituximab and alemtuzumab in lymphoma treatment. Please describe two proposed mechanisms of action for these antibodies. (1p) 9 8. Last years Nobel Prize was awarded for discoveries concerning two viruses, HIV and HPV. Infection with both of these viruses increases the risk for cancer development. Please compare and explain in what way these two viruses may promote cancer development. (4p) 10 9 Disease-related loss of weight is a common problem among cancer patients. Animal studies have shown that intake of Eicosapentaenoic acid (EPA) can improve food intake and prevent weight loss. Researchers have established a multi-center study to see whether this effect can be seen in cancer patients. In this study, n=818 cancer patients with weight loss were randomized to either 2g EPA per day (n=275), 4g EPA per day (n=272) or a placebo (n=271). Group assignment was unknown to both patients and researchers during the study. Main outcome was weight gain in kg after eight weeks. Shown below is a graphical summary of the observed data (means and standard errors) and a preliminary analysis. a. Describe the design. (1p) b. What kind of clinical trial is this? Motivate your answer. (1p) 11 c. Interpret these results: Which statistical methods have been used? What are the underlying hypotheses? What is your decision? How do the individual treatments compare? (4p) 12 Response: WeightGain Df Sum Sq Mean Sq F value Pr(>F) Group 2 285.1 142.5 5.7301 0.003379 ** Residuals 815 20272.0 24.9 --Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1 Pairwise comparisons using t tests with pooled SD data: WeightGain and Group Placebo 2g EPA 2g EPA 1.0000 4g EPA 0.0069 0.0163 P value adjustment method: bonferroni 10. Researchers plan a study to assess the relationship between a dietary choice (either vegan, lacto-ovo vegetarian, or neither) and cholesterol levels, where subjects will not be randomized to a dietary group. a. Is this an experimental or observational study? Motivate your answer briefly. (1p) b. Suggest two potential confounders for which the study should be controlled. Explain briefly what makes them confounders. (3p) 13 Advanced questions: I. i) A group of Swedish researchers has reported 19 different rodent carcinogens in coffee, and shown that high intake of black coffee caused ventricular cancer in mice. This caused headlines in the Swedish tabloids. You have decided to initiate a follow-up study to examine how this translates to humans. The design is a case-control study where you recruited cases from the cancer registry and chose random controls matched on age and sex from the general population. The data is collected with questionnaires. Below, you see the results of the study. Since age is a strong risk factor for all cancers, results and analysis are stratified by age (below or above age 65). Individuals <65 years Daily intake of black Not daily intake of coffee black coffee Cases Controls 20 15 Individuals >=65 years Daily intake of black Not daily intake of coffee black coffee 180 135 220 110 a. What would be a suitable measure of disease? (1p) b. Calculate this measure in each age group, and for the whole study population. (3p) c. Interpret your results. (2p) 180 90 14 15 ii) A colleague working in the same lab wants to compare the effect of two different COX2 inhibitors on the proliferation rate of a retinoblastoma cell line. In order to convince her skeptical supervisor, she wants to conduct a statistical power analysis, and asks for your help. Below, you see the settings she has chosen in a suitable software package: a. Describe the experiment that she has planned, including the type of analysis. (2p) b. How big is her chance to get a significant result with this experiment? (1p) c. How can she (slightly) increase the power of the experiment without changing the number of cell lines? (1p) 16 a) II. This year’s Nobel prize in Physiology and Medicine was awarded for the discovery of telomers and telomerase. i. Please describe an important process that is regulated by telomers and telomerase, and also provide a reasonable speculation on why evolution has developed the process regulated by telomers and telomerase. (5p) ii. Please hypothesize on the potential future use of the knowledge on telomere biology in the management of cancer patients, and also suggest and motivate a specific way to develop a novel anti-cancer drug based on this knowledge. (8p) 17 18 III. A deregulated cell cycle is thought to be a hallmark of cancer cells. i. Please describe the cell cycle machinery in a quiescent cell, and how this is altered as the cell enters and traverses the G1-phase of the cell cycle. (8p) ii. An over-expression of the onco-protein cyclin E is frequently observed in many tumor types. Please discuss possible mechanisms for such an over-expression. Please also explain how you can define the specific mechanism in a tumor cell line system. (6p) 19 20 IV. ”Classification is the language of medicine.” In the present lymphoma classification, ”WHO classification of tumours of haematopoietic and lymphoid tissues”, are the diagnosis based upon four different types of information. a) Which four types of information? (2p) b) Why is it so important to classify lymphomas in this way? (2p) c) In most cases it is not possible for the physician to explain why the patient got the lymphoma. But in some cases does the patient have a clear risk factor. Mention two different types of major risk-factors for lymphoma development, and suggest why they are risk factors. (2p) Follicular lymphoma (FL) and Burkitt’s lymphoma (BL) are examples of lymphomas with different chromosomal aberrations, biology, clinical picture and treatment. Typical chromosomal aberrations in these diseases are t(14;18) in FL and t(8;14) in BL. Based on this information, please reflect upon: d) The consequence of each aberration for; the affected lymphocytes, the clinical picture, treatment strategy and treatment outcome. (8p) 21 22 23