Mutant Allele and Glioblastoma

-there are 8 questions

1. Christine Chio

1. Explain the Warburg hypothesis and discuss its relevance to the altered metabolism of cancer cells.

2. Identify and describe three reasons why cancer cells might preferentially utilize aerobic glycolysis over oxidative phosphorylation.

3. Provide two examples of how changes in metabolic pathways can influence the epigenetic regulation of cancer cell fate.

2. Minah Kim

(1) Define tumor angiogenesis and vascular co-option.

(2) Outline the recognized mechanisms contributing to resistance against anti-VEGF treatment.

(3) Describe how vascular stabilization/normalization following anti-angiogenic treatment can modulate the tumor immune microenvironment.

3. Benjamin Izar

In class, we discussed how melanoma develops as a means of acquiring certain mutations, which ultimately govern transformation from normal melanocytes to melanoma cells. We reviewed an experimental model of human melanoma in which three such mutations were shown to be important for transformation, including mutations in BRAF, the promoter of TERT and loss of CDKN2A.

Question 1: Based on the example above, can you explain the terms “sufficiency” and “necessity” relating to the role of BRAF mutations in the transformation from melanocytes to melanoma. (Limit answer to ¼ of a page) Clinically, melanoma is staged based on the characteristics of the primary tumor (e.g., depth of invasion, presence of ulceration) and the involvement of other organs (e.g., lymph nodes, distant metastases). A critical aspect of tumor staging is the presence or absence of a tumor-involved “sentinel lymph node”.

Question 2: Explain what the “sentinel lymph node” is and how this affects staging of melanoma. (Limit answer to ¼ of a page) Advanced melanoma is an archetypical disease in the understanding of how oncogene-directed and immunebased therapies may work and how tumors develop resistance to such therapies. Frequently, mechanisms of resistance discovered in melanoma are also found in other cancer types treated with the same type of therapy. Thus, understanding mechanisms of resistance in melanoma provides important, foundational insights.

Question 3:

3.1: Explain the concept of “bypass pathway activation” as a mechanism of resistance to targeted, BRAF V600E-directed therapies.

3.2: Provide two examples for mechanisms of resistance to immunotherapies. (Bonus question 3.3): Explain the concept of “lineage de-differentiation” in the context of targeted, BRAF V600E-directed therapies. (Limit answers to ½ of a page)

4. Robert Schwabe

Question: Immunotherapy has revolutionized many aspects of cancer therapy.

Please describe

(i) the concept of hot and cold tumors;

(ii) how immune checkpoint inhibitor (ICI) therapy works; and

(iii) what factors influence the success of ICI therapy. (questions continued on following page)

5. Peter Sims

A) In class, we discussed how bulk and single-cell methods for analyzing single-nucleotide variants (SNVs) differ in how variant allele frequencies (VAFs) are computed. Describe this difference.

B) Relatedly, we also discussed a study that compared the frequencies of certain clones in a tumor sample as measured by single-cell DNA sequencing to the frequencies inferred from bulk DNA sequencing of the same sample. Give two (and not more than two) reasons why clonal frequencies measured by single-cell DNA sequencing might differ from those inferred from bulk sequencing measurements.

6. Wei Gu

The prevalence of TP53 gene mutation in human cancers suggests an important function of p53 in tumor suppression. Evidence from both in vitro and in vivo experiments has established the pivotal role of p53 in cell fate decisions and tumor suppression. p53 is a central tumor suppressor that responds to diverse stress signals by orchestrating specific cellular responses with multiple mechanisms. The p53 protein achieves diverse cellular outcomes by selectively modulating the expression of certain target genes, and many of them are directly associated with its tumor suppression activities. Inactivation of the p53 tumor suppression pathway is a pivotal event in the formation of most human cancers. Why was p53 initially identified as an oncogene more than forty years ago? Please list at least four different mechanisms of p53-mediated tumor suppression.

7. Anil Rustgi

Sporadic colorectal cancer involves the accumulation of mutations in oncogenes and tumor suppressor genes. Critical events relate to abnormal Wnt signaling (e.g., APC mutations), Kras mutations and p53 mutations. About 15% of cases harbor microsatellite instability. What are the mechanisms underlying DNA mismatch repair and how do mutations in the reparative genes (enzymes) promote microsatellite instability? What are the consequences of microsatellite instability? How can microsatellite instability in tumors be diagnosed? What is the condition or syndrome called if the mutations occur at the germline level? Finally, how have the adverse consequences been exploited therapeutically?

8. Zhiguo Zhang

A genome-wide association study (GWAS) indicates that a mutant allele is associated with glioblastoma. Surprisingly, the mutant allele occurs at an intergenic region. You hypothesize that this mutant allele affects the expression of a tumor suppressor gene. Please design experiments to identify the tumor suppressor gene and discuss the potential impact of the mutant allele on the expression of this tumor suppressor gene.

--essay-type
-1 page PER question
-answers to be 1 typed page or less (single-spaced, font 11pt or higher, preferred fonts-Arial, Times New Roman, Calibri
-figures or illustrations allowed and you may put them in additional page(s)
-references or citations are recommended and you may put them in additional page(s)
-exam is open book, you are welcome to look at class notes, textbooks, pubmed and other sources.
-discussion with each other is NOT permitted, it may constitute plagiarism and you may get a bad grade
-please do not quote class notes or any other source verbatim, use your own words to convey your answer, if you absolutely must quote, then use quotation marks (" ") and cite the source that you are quoting