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Chapter 1: Cancer and the Genome

A 33-year-old woman is diagnosed with breast cancer. Given the early age of onset, BRCA1/2 sequencing is requested on a peripheral blood sample to determine whether she has an inherited cancer predisposition syndrome. This study identifies a mutation in BRCA1 that alters codon 1443 as follows:

  • Normal sequence: CGA

  • Mutated sequence: TGA

Using the codon chart in Figure 1-6, determine the nature of this mutation.

A. Nonsense mutation

B. Missense mutation

C. Silent mutation

D. Frameshift mutation

Answer: A

Explanation: The normal CGA codon encodes for an arginine amino acid. The patient has a substitution mutation that changes the cytosine in the first position to a thymine. The resultant TGA codon is a stop codon, which terminates translation. This type of mutation is called a nonsense mutation (A). Missense mutations (B) change one amino acid to another. Silent mutations change the sequence from one codon that encodes for a particular amino acid to another codon that encodes for the same amino acid. For instance, mutation from an AGA codon to an AGG codon would be a silent mutation, because both codons encode for arginine. Finally, frameshift mutations require insertion or deletion of bases in the sequence, which alters the reading frame.

A 47-year-old woman is newly diagnosed with AML. To further classify her leukemia, a number of genetic studies are performed, including sequencing of a large panel of genes implicated in myeloid malignancy. Which of the following mutations are most likely to be a passenger mutation?

A. A loss-of-function substitution mutation in the TP53 tumor suppressor gene

B. Monosomy of chromosome 17, the chromosome where TP53 resides

C. A gain-of-function missense mutation in the IDH1 oncogene

D. A silent mutation in the IDH1 oncogene

Answer: D

Explanation: Driver mutations are mutations that provide a selective advantage to tumor cells, promoting their growth and survival. In contrast, passenger mutations arise are functionally inconsequential mutations that arise incidentally in tumor cells due to compromised quality control of DNA replication and repair. Mutations that inactivate tumor suppressor genes (A, B) and mutations that activate oncogenes (C) confer a growth advantage and promote malignancy. As such, they represent driver mutations. In contrast, silent mutations—regardless of the gene affected—are not likely to have any impact on gene function, because there is no change in the ...

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