19. Cancer Genetics

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.

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.

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.

Explain why individuals with XP show such an early age of onset. 

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. 

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?