“Genetic Alterations During Colorectal-Tumor Development”
N. Engl. J. Med. 319, 525–532.
Abstract
Methods
1. Using the data presented in Table 1, calculate the totals and percentage of Class I, Class II, Class III and Carcinoma specimens that are positive for Ras gene mutations and answer the following questions.
- What is a mutation?
Mutations are permanent changes in the DNA. They do not always lead to an altered protein or RNA product. Mutations can occur anywhere in the genome; not just in a region defined as a “gene”. Mutations occur at the level of DNA; a mistake in the transcription or translation process results in a mistake in one copy of a product (mRNA and/or protein) which is not a mutation.
- How do you interpret the “Mutation” column in Table 1?
The investigators are pointing out the location (Codon 12, Codon 13, etc…) of the ras mutations. Students may point out that K-ras and N-ras genes are different genes within the ras family. The investigators are also demonstrating the actual DNA change (GGT = wild-type, GAT = mutation) and how the DNA change leads to a different amino acid in the final ras protein product (GLY to ASP).
2. According to Table 1, what class (es) of tumors has the highest frequencies of Ras mutations?
Only 12.5% of Class I tumors have ras mutations while Classes II, III and carcinomas have 42%, 57.1% and 46.7%, respectively. While Class III tumors have the highest true percentage, students should notice the low frequency of ras mutations in Class I adenomas compared to the other types.
3. Analyze the data presented in Table 2. What histopathological feature of adenomasis most highly correlated with Ras mutations?
Tumor size seems to correlate most strongly with ras gene mutations. Tumors that are greater than 2cm have a higher frequency of ras mutations regardless of tumor class or other histopathological features.
Some students, who have taken a histology course or have other experience, may be more comfortable with the terminology describing the morphology (tubular, villous) and level of dysplasia. Students can usually resolve their confusion by discussion (with peers and instructor) or looking up these terms if they need to. It is not a major point that students know exactly how “tubulovillous” specimens appear.
4. Vogelstein et al. investigated allelic deletions in colorectal tumors at three different chromosomal locations. The data is presented in Table 3. In 1988 the genes of significance located on 5q, 18q, and 17p had not yet been identified.
What broad class of genes are most likely located in these regions of chromosome loss? Explain your reasoning.
Because these loci have been deleted (or “lost”) in tumor specimens, one would suspect that Tumor suppressor genes or other growth-suppressor gene would most likely be found in these regions. Proto-oncogenes (or oncogenes), or other pro-growth genes would not be likely candidates as their “loss” would not offer a selective advantage to rapidly dividing tumor cells.
Instructors can also point out that the human genome was decades away from being completely sequenced at the time of this publication (1988) and our knowledge of genome mapping was much less than it is now. Instructors may point out that, in reality, more than one gene was probably located at the chromosomal regions described (5q, 18q, 17p).
5. Use the data presented in Tables 1 and 3 to create a figure that shows the percentage of each type of genetic abnormality found in each type of tumor (Class I, Class II, Class III and Carcinoma). Include an appropriate figure description.
Figure X. ______
6. Based on the data presented in this paper, construct a model of colon tumorigenesis showing where the four genetic alterations (ras mutation, 5q, 18q, and 17p) are most likely located on the pathway.
7. What are scientific models? Explain why scientists create and use scientific models.
Answers will vary but students should recognizethat models allow scientists to:
-communicate their ideas about a particular phenomenon
-evaluate/compare experimental data with existing models
-ask new questions and design new experiments about a particular phenomenon
-frame or anchor a variety of data/results in a logical way
Students may also recognize that the term “model” can refer todifferent things depending on the situation. Some examples may include:
-physical, hand-held objects
-computer or mathematical algorithms
-schematic diagrams or drawings
-computer-generated images or animations
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