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Ch. 24 - Cancer Genetics

Chapter 23, Problem 27

What evidence indicates that mutations in human DNA mismatch repair genes are related to certain forms of cancer?

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Hi everybody, let's take a look at this practice problem together, the deficiency of the D. N. A. Mismatch repair system in tumors that are associated with lynch syndrome can be detected by now, lynch syndrome recall is a colorectal cancer and the DNA mismatch repair system repairs mismatched base pairs by exercising out the incorrect base and inserting in the correct one. So a deficiency in the system is going to lead to mutations in D. N. A. Note that all of our answers include the word micro satellite instability. What is a micro satellite? Well, a micro satellite is repeated short DNA sequences occurring in a row. And there's a test called micro satellite instability, which is a test for lynch syndrome, likelihood. The more micro satellite, excuse me, the more micro satellite instability, the more likelihood of the person having lynch syndrome due to an accumulation of mutations that would occur from the deficient DNA repair system. So let's take a look at our options. A low micro satellite instability would be an inconclusive test. It would show that there are some changes in the micro satellite but not enough to determine if the person had lynch syndrome. A stable micro satellite instability indicates that a person is unlikely to have lynch syndrome because they're not having a bunch of mutations occurring. A high micro satellite instability suggests that a person has high likelihood. So it is likely that they have lynched syndrome and that's because there would be a high number of changes. And so our answer is a high micro satellite instability. Alright, everybody, I hope you found this helpful and I'll see you soon for the next practice problem.
Related Practice
Textbook Question

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?

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Textbook Question

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 do not develop CML.

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Textbook Question

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 develop 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, and (c) if the addition of a normal RB1 gene will change the cancer-causing potential of osteosarcoma cells?

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Textbook Question

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.

Predisposing Mutations in BRCA1
Kindred    Codon    Nucleotide     Coding Effect     Frequency in
                               Change                                    Control
                                                                                Chromosomes    
 1901          24           -11 bp          Frameshift           0/180
                                                       or splice
 2082        1313         C→T           Gln→Stop            0/170
 1910        1756         Extra C        Frameshift           0/162
 2099        1775         T→G            Met→Arg            0/120
 2035         NA*          ?                  Loss of                NA*
                                                       transcript                                      _
Source: (1994). Science 266:66–71. © AAAS.

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.

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Textbook Question

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.

Predisposing Mutations in BRCA1
Kindred    Codon    Nucleotide     Coding Effect     Frequency in
                               Change                                    Control
                                                                                Chromosomes    
 1901          24           -11 bp          Frameshift           0/180
                                                       or splice
 2082        1313         C→T           Gln→Stop            0/170
 1910        1756         Extra C        Frameshift           0/162
 2099        1775         T→G            Met→Arg            0/120
 2035         NA*          ?                  Loss of                NA*
                                                       transcript                                      _
Source: (1994). Science 266:66–71. © AAAS.

Examine the types of mutations that are listed in the table, and determine if the BRCA1 gene is likely to be a tumor-suppressor gene or an oncogene.

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Textbook Question

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.

Predisposing Mutations in BRCA1
Kindred    Codon    Nucleotide     Coding Effect     Frequency in
                               Change                                    Control
                                                                                Chromosomes    
 1901          24           -11 bp          Frameshift           0/180
                                                       or splice
 2082        1313         C→T           Gln→Stop            0/170
 1910        1756         Extra C        Frameshift           0/162
 2099        1775         T→G            Met→Arg            0/120
 2035         NA*          ?                  Loss of                NA*
                                                       transcript                                      _
Source: (1994). Science 266:66–71. © AAAS.

Although the mutations listed in the table are clearly deleterious and cause breast cancer in women at very young ages, each of the kindred groups had at least one woman who carried the mutation but lived until age 80 without developing cancer. Name at least two different mechanisms (or variables) that could underlie variation in the expression of a mutant phenotype, and propose an explanation for the incomplete penetrance of this mutation. How do these mechanisms or variables relate to this explanation?

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