Transcript The Biology of Cancer

Building a Model of Tumorigenesis:
A small group activity for a Cancer
Biology/Cell Biology course
L. K. Wright
Supplemental File : Multistep
Tumorigenesis Slides
Human tumorigenesis is a multi-step
process.
Human tumor development as a multi-step
process has been most clearly documented
in the intestinal epithelium (colon)
Insert diagram of human colon here
http://www.webmd.com/digestive-disorders/picture-ofthe-colon
The instructor may want to include images of
normal colon vs colon cancer here for a
comparison.
Evidence supports the idea of a “pre-cursor--product” relationship
Normal colon epithelium
colon hyperplasia
colon dysplasia
colon adenoma (polyp)
colorectal carcinoma
Evidence #1: Clinical studies of patients who
have undergone removal of colon polyps
demonstrate lower-than-expected cumulative
incidences of colorectal cancer.
Cumulative Incidence of Colorectal Cancer in the National Polyp Study Cohort.
The instructor would show Figure 1 (Cumulative
Incidence of Colorectal Cancer in the National Polyp
Study Cohort) from
Winawer, S.J., Zauber, A.G., Ho, M.N., O’Brien, M.J.,
Gottlieb, L.S., Sternberg, S.S., Waye, J.D., Schapiro, M.,
Bond, J.H., Panish, J.F., et al. (1993). Prevention of
Colorectal Cancer by Colonoscopic Polypectomy. N.
Engl. J. Med. 329, 1977–1981.
http://www.nejm.org/doi/full/10.1056/NEJM199312
303292701
Evidence #2: Nearly 100% of individuals with
Familial adenomatous polyposis (FAP) will
develop colorectal carcinoma, if not treated.
Familial adenomatous polyposis (FAP)
• FAP is an inherited/familial cancer syndrome.
• People with FAP have a somatic mutation in one copy
of the APC (adenomatous polyposis coli) Tumor
Suppressor Gene on chromosome 5
• People with FAP present with hundreds of colon
polyps (adenomas) by early adulthood.
• 100% of people with FAP will develop colon carcinoma
if not treated.
Colon of familial adenomatous
polyposis coli patient compared to
normal colon. (A) The polyposis
colon is completely covered by
hundreds of projecting polyps each
resembling a tiny cauliflower when
viewed with the naked eye. (B) The
normal colon wall is a gently
undulating but smooth surface.
(Courtesy of Andrew Wyllie and Mark
Arends.)
Images from:
http://www.ncbi.nlm.nih.gov/books/NBK2690
2/figure/A4344/
Question: What’s the problem with all of these
tiny polyps in FAP patients?
NORMAL CELL
Mutation inactivates tumor
suppressor genes
One pathway of
multi-step
tumorigenesis
looks like this
Cells proliferate
Mutation inactivates DNA repair genes
Mutation of proto-oncogene results in an
oncogene
Mutation(s) inactivate(s)more tumor
suppressor genes
CANCER
Mutation inactivates tumor suppressor
genes
What are the
genetic
alterations that
occur at each
step in the
pathway?
Cells proliferate
Mutation inactivates DNA repair genes
Mutation of proto-oncogene results in an
oncogene
Mutation(s) inactivate(s)more tumor
suppressor genes
CANCER
Think/pair/share
How would you
design a study to
uncover the genetic
changes that occur
during
tumorigenesis of a
specific cancer
type?
Mutation inactivates tumor suppressor
genes
Cells proliferate
Mutation inactivates DNA repair genes
Mutation of proto-oncogene results in an
oncogene
Mutation(s) inactivate(s)more tumor
suppressor genes
CANCER
We are going to do an activity based on a
paper from The New England Journal of
Medicine entitled:
“Genetic Alterations During Colorectal-Tumor
Development”
As part of this activity you will be
constructing a scientific model. What is a
“scientific model”? Why are they useful?
In the paper tumors are classified as…
Normal
epithelium
Early
adenoma
Intermediate
adenoma
Late
adenoma
Class I
Class II
Class III
= normal cell
= tumor cell
Carcinoma
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.
a. What is a mutation?
b. How do you interpret the “Mutation” column in Table 1?
2. According to Table 1, what class (es) of tumors has the
highest frequencies of Ras mutations?
3. Analyze the data presented in Table 2. What
histopathological feature of adenomas is most highly
correlated with Ras mutations?
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.
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.
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.
This model was published in 1990 (by the same
research lab)
5q mutation
or loss
FAP
Ras
mutation
DNA hypomethylation
18q
loss
17p
Loss
p53
Other
alterations