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Ch. 24 - Cancer Genetics
Klug - Concepts of Genetics 12th Edition
Klug12th EditionConcepts of Genetics ISBN: 9780135564776Not the one you use?Change textbook
All textbooksKlug 12th EditionCh. 24 - Cancer GeneticsProblem 26
Chapter 24, Problem 26

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.

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Step 1: Understand the nature of the BCR-ABL fusion gene. This gene results from a chromosomal translocation between chromosomes 9 and 22, creating the Philadelphia chromosome, which produces a constitutively active tyrosine kinase implicated in CML development.
Step 2: Recognize that the presence of the BCR-ABL fusion gene transcript indicates that the gene is transcriptionally active, meaning it is being transcribed into RNA, but this alone does not guarantee disease manifestation.
Step 3: Consider the concept of clonal expansion and additional mutations. For CML to develop, cells carrying the BCR-ABL fusion gene must undergo clonal expansion and acquire further genetic or epigenetic changes that promote uncontrolled proliferation and leukemogenesis.
Step 4: Explore the possibility of immune surveillance and cellular control mechanisms. Healthy individuals may have immune systems or cellular regulatory pathways that suppress or eliminate cells expressing the fusion gene before they can cause disease.
Step 5: Conclude that the detection of BCR-ABL transcripts in healthy adults likely reflects low-level, transient, or non-pathogenic expression of the fusion gene without the necessary secondary events or cellular environment required for CML development.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

BCR-ABL Fusion Gene and Its Role in CML

The BCR-ABL fusion gene results from a translocation between chromosomes 9 and 22, creating the Philadelphia chromosome. This fusion gene encodes a constitutively active tyrosine kinase that drives uncontrolled cell proliferation, a hallmark of chronic myelogenous leukemia (CML). However, presence of the gene alone does not guarantee disease development.
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Clonal Expansion and Additional Genetic Events

For CML to develop, cells carrying the BCR-ABL fusion must undergo clonal expansion and acquire additional mutations or epigenetic changes. These secondary events promote malignant transformation and disease progression, explaining why some individuals with the fusion gene remain healthy without developing leukemia.
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Gene Expression Regulation and Cellular Context

Although the BCR-ABL fusion gene may be transcriptionally active, its expression level, cellular environment, and regulatory mechanisms influence whether it causes disease. In healthy individuals, factors such as immune surveillance and controlled gene expression can prevent the fusion protein from triggering leukemogenesis.
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Related Practice
Textbook Question

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.

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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

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.

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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 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?

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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.

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.

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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