Chapter 23, Problem 28
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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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?
What evidence indicates that mutations in human DNA mismatch repair genes are related to certain forms of cancer?
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.
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?
Researchers have identified some tumors that have no recurrent mutations or deletions in known oncogenes or tumor-suppressor genes and no detectable epigenetic alterations. However, these tumors often have large chromosomal deletions. What are some possible explanations that could account for the genetic causes behind these tumors?
Skin cancer carries a lifetime risk nearly equal to that of all other cancers combined. Following is a graph [modified from K. H. Kraemer (1997). Proc. Natl. Acad. Sci. (USA) 94:11–14] depicting the age of onset of skin cancers in patients with or without XP, where the cumulative percentage of skin cancer is plotted against age. The non-XP curve is based on 29,757 cancers surveyed by the National Cancer Institute, and the curve representing those with XP is based on 63 skin cancers from the Xeroderma Pigmentosum Registry.
Provide an overview of the information contained in the graph.