How do we know that malignant tumors arise from a single cell that contains mutations?

How do we know that cancer development requires more than one mutation?

How do we know that cancer cells contain defects in DNA repair?

Where are the major regulatory points in the cell cycle?

List the functions of kinases and cyclins, and describe how they interact to cause cells to move through the cell cycle.

How can mutations in non-coding segments of DNA contribute to the development of cancers?

What is the difference between saying that cancer is inherited and saying that the predisposition to cancer is inherited?

As a genetic counselor, you are asked to assess the risk for a couple with a family history of familial adenomatous polyposis (FAP) who are thinking about having children. Neither the husband nor the wife has colorectal cancer, but the husband has a sister with FAP. What is the probability that this couple will have a child with FAP? Are there any tests that you could recommend to help in this assessment?

What is apoptosis, and under what circumstances do cells undergo this process?

Define tumor-suppressor genes. Why is a mutated single copy of a tumor-suppressor gene expected to behave as a recessive gene?

Describe the steps by which the TP53 gene responds to DNA damage and/or cellular stress to promote cell-cycle arrest and apoptosis. Given that TP53 is a recessive gene and is not located on the X chromosome, why would people who inherit just one mutant copy of a recessive tumor-suppressor gene be at higher risk of developing cancer than those without the recessive gene?

Part of the Ras protein is associated with the plasma membrane, and part extends into the cytoplasm. How does the Ras protein transmit a signal from outside the cell into the cytoplasm? What happens in cases where the ras gene is mutated?

If a cell suffers damage to its DNA while in S phase, how can this damage be repaired before the cell enters mitosis?

Distinguish between oncogenes and proto-oncogenes. In what ways can proto-oncogenes be converted to oncogenes?

Of the two classes of genes associated with cancer, tumor-suppressor genes and oncogenes, mutations in which group can be considered gain-of-function mutations? In which group are the loss-of-function mutations? Explain.

How do translocations such as the Philadelphia chromosome contribute to cancer?

Explain why many oncogenic viruses contain genes whose products interact with tumor-suppressor proteins.

DNA sequencing has provided data to indicate that cancer cells may contain tens of thousands of somatic mutations, only some of which confer a growth advantage to a cancer cell. How do scientists describe and categorize these recently discovered populations of mutations in cancer cells?

How do normal cells protect themselves from accumulating mutations in genes that could lead to cancer? How do cancer cells differ from normal cells in these processes?

Describe the difference between an acute transforming virus and a virus that does not cause tumors.

Epigenetics is a relatively new area of genetics with a focus on phenomena that affect gene expression but do not affect DNA sequence. Epigenetic effects are quasi-stable and may be passed to progeny somatic or germ-line cells. What are known causes of epigenetic effects, and how do they relate to cancer?

Radiotherapy (treatment with ionizing radiation) is one of the most effective current cancer treatments. It works by damaging DNA and other cellular components. In which ways could radiotherapy control or cure cancer, and why does radiotherapy often have significant side effects?

Genetic tests that detect mutations in the BRCA1 and BRCA2 tumor-suppressor genes are widely available. These tests reveal a number of mutations in these genes—mutations that have been linked to familial breast cancer. Assume that a young woman in a suspected breast cancer family takes the BRCA1 and BRCA2 genetic tests and receives negative results. That is, she does not test positive for the mutant alleles of BRCA1 or BRCA2. Can she consider herself free of risk for breast cancer?

Explain the apparent paradox that both hypermethylation and hypomethylation of DNA are often found in the same cancer cell.

As part of a cancer research project, you have discovered a gene that is mutated in many metastatic tumors. After determining the DNA sequence of this gene, you compare the sequence with those of other genes in the human genome sequence database. Your gene appears to code for an amino acid sequence that resembles sequences found in some serine proteases. Conjecture how your new gene might contribute to the development of highly invasive cancers.

Mutations in tumor-suppressor genes are associated with many types of cancers. In addition, epigenetic changes (such as DNA methylation) of tumor-suppressor genes are also associated with tumorigenesis [Otani et al. (2013).

Expert Rev Mol Diagn 13:445-455].

How might hypermethylation of the TP53 gene promoter influence tumorigenesis?

Mutations in tumor-suppressor genes are associated with many types of cancers. In addition, epigenetic changes (such as DNA methylation) of tumor-suppressor genes are also associated with tumorigenesis [Otani et al. (2013). Expert Rev Mol Diagn 13:445 455].

Knowing that tumors release free DNA into certain surrounding body fluids through necrosis and apoptosis, Kloten et al. [(2013). Breast Cancer Res. 15(1):R4] outlines an experimental protocol for using human blood as a biomarker for cancer and as a method for monitoring the progression of cancer in an individual.

A study by Bose and colleagues (1998). Blood 92:3362-3367] and a previous study by Biernaux and others (1996). Bone Marrow Transplant 17:(Suppl. 3) S45–S47] showed that BCR-ABL fusion gene transcripts can be detected in 25 to 30 percent of healthy adults who do not develop chronic myelogenous leukemia (CML). Explain how these individuals can carry a fusion gene that is transcriptionally active and yet does not develop CML.

Those who inherit a mutant allele of the RB1 tumor-suppressor gene are at risk for developing a bone cancer called osteosarcoma. You suspect that in these cases, osteosarcoma requires a mutation in the second RB1 allele, and you have cultured some osteosarcoma cells and obtained a cDNA clone of a normal human RB1 gene. A colleague sends you a research paper revealing that a strain of cancer-prone mice develops malignant tumors when injected with osteosarcoma cells, and you obtain these mice. Using these three resources, what experiments would you perform to determine:

(a) Whether osteosarcoma cells carry two RB1 mutations

(b) Whether osteosarcoma cells produce any pRB protein

(c) If the addition of a normal RB1 gene will change the cancer-causing potential of osteosarcoma cells?

The table in this problem summarizes some of the data that have been collected on mutations in the BRCA1 tumor-suppressor gene in families with a high incidence of both early-onset breast cancer and ovarian cancer.

Note the coding effect of the mutation found in kindred group 2082. This results from a single base-pair substitution. Draw the normal double-stranded DNA sequence for this codon (with the 5' and 3' ends labeled), and show the sequence of events that generated this mutation, assuming that it resulted from an uncorrected mismatch event during DNA replication.