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5: Colorectal Cancer Arises Through the Sequential Mutation of a Number of Genes
Loss of normal tumorsuppressor gene APC
1 A polyp (small growth)
forms on the colon wall.
2 A benign, precancerous
3 An adenoma
(benign tumor) grows.
Loss of tumorsuppressor gene p53
4 A carcinoma (malignant
Other changes; loss of
5 The cancer metastasizes
(spreads to other tissue
through the bloodstream).
15.12 Mutations in multiple genes contribute
to the progression of colorectal cancer.
the cells of the polyp acquire the abnormal characteristics of
cancer cells. In the later stages of the disease, the tumor may
invade the muscle layer surrounding the gut and metastasize.
The progression of the disease is slow; from 10 to 35 years
may be required for a benign tumor to develop into a malignant tumor.
Most cases of colorectal cancer are sporadic, developing
in people with no family history of the disease, but a few
families display a clear genetic predisposition to this disease.
In one form of hereditary colon cancer, known as familial
adenomatous polyposis coli, hundreds or thousands of
polyps develop in the colon and rectum; if these polyps are
not removed, one or more almost invariably become
Because polyps and tumors of the colon and rectum
can be easily observed and removed with a colonoscope (a
fiber-optic instrument used to view the interior of the rectum and colon), much is known about the progression of
colorectal cancer, and some of the genes responsible for its
clonal evolution have been identified. Mutations in these
genes are responsible for the different steps of colorectalcancer progression. One of the earliest steps is a mutation
that inactivates the APC gene, which increases the rate of
cell division, leading to polyp formation (see Figure 15.12).
A person with familial adenomatous polyposis coli inherits
one defective copy of the APC gene, and defects in this gene
are associated with the numerous polyps that appear in
those who have this disorder. Mutations in APC are also
found in the polyps that develop in people who do not have
adenomatous polyposis coli.
Mutations of the ras oncogene usually occur later, in
larger polyps consisting of cells that have acquired some
genetic mutations. The normal ras proto-oncogene is a key
player in a pathway that relays signals from growth factors to
the nucleus, where the signal stimulates cell divsion. When
ras is mutated, the protein that it encodes continually relays
a stimulatory signal for cell division, even when growth factor is absent.
Mutations in p53 and other genes appear still later in
tumor progression; these mutations are rare in polyps but
common in malignant cells. About 75% of colorectal cancers have mutations in tumor-suppressor gene p53.
Because p53 prevents the replication of cells with genetic
damage and controls proper chromosome segregation,
mutations in p53 may allow a cell to rapidly acquire further
gene and chromosome mutations, which then contribute
to further proliferation and invasion into surrounding
The sequence of steps just outlined is not the only
route to colorectal cancer, and the mutations need not
occur in the order presented here, but this sequence is a
common pathway by which colon and rectal cells become
• Cancer is fundamentally a genetic disorder, arising from
somatic mutations in multiple genes that affect cell division
and proliferation. If one or more mutations are inherited, then
fewer additional mutations are required for cancer to develop.
A mutation that allows a cell to divide rapidly provides the cell
with a growth advantage; this cell gives rise to a clone of cells
having the same mutation. Within this clone, other mutations
occur that provide additional growth advantages, and cells
with these additional mutations become dominant in the
clone. In this way, the clone evolves.
Environmental factors play an important role in the
development of many cancers by increasing the rate of
Oncogenes are dominant mutated copies of normal genes
(proto-oncogenes) that normally stimulate cell division.
Tumor-suppressor genes normally inhibit cell division;
recessive mutations in these genes may contribute to cancer.
Sometimes, the mutation of a single allele of a tumorsuppressor gene is sufficient to cause cancer, a phenomenon
known as haploinsufficiency.
The cell cycle is controlled by cyclins and cyclin-dependent
kinases. Mutations in genes that control the cell cycle are often
associated with cancer.
• Defects in DNA-repair genes often increase the overall
mutation rate of other genes, leading to defects in protooncogenes and tumor-suppressor genes that may contribute
to cancer progression.
Mutations in sequences that regulate telomerase allows cells to
divide indefinitely, contributing to cancer progression. Tumor
progression is also affected by mutations in genes that
promote vascularization and the spread of tumors.
Some cancers are associated with specific chromosome
mutations, including chromosome deletions, inversions, and
translocations. Mutations in some genes cause or allow the
missegregation of chromosomes, leading to aneuploidy that
may contribute to cancer.
Viruses are associated with some cancers; they contribute to
cell proliferation by mutating and rearranging host genes and
by altering the expression of host genes.
• Colorectal cancer offers a model system for understanding
tumor progression in humans. Initial mutations stimulate
cell division, leading to a small benign polyp. Additional
mutations allow the polyp to enlarge, invade the muscle
layer of the gut, and eventually spread to other sites.
Mutations in particular genes affect different stages
of this progression.
malignant tumor (p. 391)
metastasis (p. 391)
clonal evolution (p. 392)
oncogene (p. 394)
tumor-suppressor gene (p. 394)
proto-oncogene (p. 394)
loss of heterozygosity (p. 395)
haploinsufficiency (p. 396)
cyclin-dependent kinase (CDK)
cyclin (p. 397)
human papilloma virus (HPV) (p. 400)
Answers to Concept Checks
1. Retinoblastoma results from at least two separate genetic
defects, both of which are necessary for cancer to develop. In
sporadic cases, two successive mutations must occur in a single
cell, which is unlikely and therefore typically occurs in only one
eye. In people who have inherited one of the two required
mutations, every cell contains this mutation so that a single
additional mutation is all that is required for cancer to develop.
Given the millions of cells in each eye, there is a high probability
that the second mutation will occur in at least one cell of each
eye, producing tumors in both eyes and the inheritance of this
type of retinoblastoma.
2. Oncogenes have a stimulatory effect on cell proliferation.
Mutations in oncogenes are usually dominant because a
mutation in a single copy of the gene is usually sufficient to
produce a stimulatory effect. Tumor-suppressor genes inhibit cell
proliferation. Mutations in tumor-suppressor genes are generally
recessive, because both copies must be mutated to remove all
1. In some cancer cells, a specific gene has become duplicated
many times. Is this gene likely to be an oncogene or a tumorsuppressor gene? Explain your reasoning.
The gene is likely to be an oncogene. Oncogenes stimulate cell
proliferation and act in a dominant manner. Therefore, extra
copies of an oncogene will result in cell proliferation and cancer.
Tumor-suppressor genes, on the other hand, suppress cell
proliferation and act in a recessive manner; a single copy of a
tumor-suppressor gene is sufficient to prevent cell proliferation.
Therefore, extra copies of the tumor-suppressor gene will not
lead to cancer.
*1. What types of evidence indicate that cancer arises from
2. How is it true that many types of cancer are genetic and yet
*3. Outline Knudson’s multistage theory of cancer and describe
how it helps to explain unilateral and bilateral cases of
4. Briefly explain how cancer arises through clonal evolution.
8. Why do mutations in genes that encode DNA-repair
enzymes often produce a predisposition to cancer?
*9. What role do telomeres and telomerase play in cancer
*10. Explain how chromosome deletions, inversions, and
translocations may cause cancer.
11. Briefly outline how the Philadelphia chromosome leads to
chronic myelogenous cancer.
12. What is genomic instability? Give some ways in which
genomic instability may arise.
*5. What is the difference between an oncogene and a tumorsuppressor gene? Give some examples of the functions of
proto-oncogenes and tumor suppressers in normal cells.
*6. How do cyclins and CDKs differ? How do they interact in
controlling the cell cycle?
7. Briefly outline the events that control the progression of
cells through the G1/S checkpoint in the cell cycle.
*13. How do viruses contribute to cancer?
14. Briefly outline some of the genetic changes that are
commonly associated with the progression of colorectal
Application Questions and Problems
*15. The palladin gene, which plays a role in pancreatic cancer
(see the introduction to this chapter), is said to be an
oncogene. Which of its characteristics suggest that it is
an oncogene rather than a tumor-suppressor gene?
*18. A couple has one child with bilateral retinoblastoma. The
mother is free from cancer, but the father has unilateral
retinoblastoma and he has a brother who has bilateral
a. If the couple has another child, what is the probability
that this next child will have retinoblastoma?
b. If the next child has retinoblastoma, is it likely to be
bilateral or unilateral?
c. Explain why the father’s case of retinoblastoma is
unilateral, whereas his son’s and brother’s cases are
16. If cancer is fundamentally a genetic disease, how might an
environmental factor such as smoking cause cancer?
17. Both genes and environmental factors contribute to cancer.
Table 15.2 shows that prostate cancer is 39 times as
common among Caucasians in Utah as among Chinese
in Shanghai. Briefly outline how you might go about
determining if these differences in the incidence
of prostate cancer are due to differences in the genetic
makeup of two populations or to differences in their
19. Mutations in the RB gene are often associated with cancer.
Explain how a mutation that results in a nonfunctional RB
protein contributes to cancer.
20. Cells in a tumor contain mutated copies of a particular gene
that promotes tumor growth. Gene therapy can be used to
introduce a normal copy of this gene into the tumor cells.
Would you expect this therapy to be effective if the mutated
gene were an oncogene? A tumor-suppressor gene? Explain
21. Radiation is known to cause cancer, yet radiation is often
used as treatment for some types of cancer. How can
radiation be a contributor to both the cause and the
treatment of cancer?
22. Some cancers are consistently associated with the deletion
of a particular part of a chromosome. Does the deleted
region contain an oncogene or a tumor-suppressor gene?
23. Many cancer cells are immortal (will divide indefinitely)
because they have mutations that allow telomerase to be
expressed. How might this knowledge be used to design
24. Bloom syndrome is an autosomal recessive disease that
exhibits haploinsufficiency. As described on page 396,
a recent survey showed that people heterozygous for
mutations at the BLM locus are at increased risk of colon
cancer. Suppose you are a genetic counselor. A young
woman is referred to you whose mother has Bloom
syndrome; the young woman’s father has no family history
of Bloom syndrome. The young woman asks whether she is
likely to experience any other health problems associated
with her family history of Bloom syndrome. What advice
would you give her?
25. Imagine that you discover a large family in which bladder
cancer is inherited as an autosomal dominant trait. Briefly
outline a series of studies that you might conduct to identify
the gene that causes bladder cancer in this family.
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Porkier Pigs Through
hat makes a bigger and tastier pig? The answer to
this question is worth billions of dollars to the pork
industry. Weight in pigs entails muscle growth and fat deposition and is influenced by a combination of genes and environmental factors. Consumers today expect pork with less
fat, and pork producers have responded: today’s pigs have
50% less fat than the typical pig of the 1950s. Identifying the
genes that promote muscle mass and growth is critical to
producing larger, leaner pigs and has long been the goal of
Muscle mass in pigs is not, however, a simple genetic
characteristic such as seed shape in peas. Numerous genes
and environmental factors, such as diet, rearing practices,
and health contribute to the muscle mass of a pig. The
inheritance of muscle mass in pigs is more complex than
that of any of the characteristics that we have studied so far.
Can the inheritance of a complex characteristic such as the
Methods of quantitative genetics are being used to identify and isolate
muscle mass of pigs be studied? Is it possible to predict the
genes that are important in determining muscle mass in pigs. [USDA.]
muscle mass of a pig on the basis of its pedigree? The
answers are yes—at least in part—but these questions cannot be addressed with the methods that we used for simple genetic characteristics. Instead,
we must use statistical procedures that have been developed for analyzing complex characteristics. The genetic analysis of complex characteristics such as muscle mass in pigs is
known as quantitative genetics.
Although the mathematical methods for analyzing complex characteristics may
seem imposing at first, most people can intuitively grasp the underlying logic of quantitative genetics. We all recognize family resemblance: we talk about inheriting our father’s
height or our mother’s intelligence. Family resemblance lies at the heart of the statistical
methods used in quantitative genetics. When genes influence variation in a characteristic, related individuals resemble one another more than unrelated individuals. Closely
related individuals (such as siblings) should resemble one another more than distantly
related individuals (such as cousins). Comparing individuals with different degrees of
relatedness, then, provides information about the extent to which genes influence a
In 2003, geneticists used a combination of quantitative genetics and molecular techniques to identify and isolate chromosomal regions that play an important role in determining increased muscle mass in pigs. Chromosome regions containing genes that
influence a quantitative trait are termed quantitative trait loci (QTLs). To locate QTLs
affecting muscle mass, the geneticists started with crosses between European wild boars and
Large White domestic pigs. The alleles from some of the domestic pigs in these crosses
markedly increased muscle mass and back-fat thickness in the offspring, indicating that the
domestic pigs possess genes that stimulated muscle growth.
The geneticists then used molecular markers to map the position of the QTLs that
influence muscle mass. They were able to narrow their search for the location of one important QTL to a 250,000-bp interval on pig chromosome 2. This region is known to contain
several genes, including one for insulin-like growth factor 2 (IGF2). Because IGF2 is known
to stimulate muscle mass in mammals, the gene immediately attracted their attention. By
sequencing the IGF2 gene of the more-muscled pigs and comparing their sequences with
those from less-muscled pigs, the geneticists were able to demonstrate that a change in a
single nucleotide, from a G to an A, added 3% to 5% more meat to a pig. Interestingly, the
nucleotide change is not in a part of the gene that encodes the protein, but instead is in an
intron. Findings from further research revealed that this substitution increases the expression of IGF2 mRNA threefold in muscle cells. The increased levels of IGF2 mRNA result in
more insulin-like growth factor 2, which stimulates muscle growth and results in moremuscled, leaner pigs. This study demonstrates the power of quantitative genetics coupled
with modern molecular techniques to identify and exploit genetic variation that influences
economically important characteristics such as muscle mass in pigs.
his chapter is about the genetic analysis of complex
characteristics such as muscle mass. We begin by considering the differences between quantitative and qualitative
characteristics and why the expression of some characteristics varies continuously. We’ll see how quantitative characteristics are often influenced by many genes, each of which
has a small effect on the phenotype. Next, we will examine
statistical procedures for describing and analyzing quantitative characteristics. We will consider the question of how
much of phenotypic variation can be attributed to genetic
and environmental influences and will conclude by looking
at the effects of selection on quantitative characteristics. Of
importance, however, is that we recognize that the methods
of quantitative genetics are not designed to identify individual genes and genotypes. Rather, the focus is on statistical
predictions based on groups of individuals.
continuous characteristics; they are also called quantitative
characteristics because any individual’s phenotype must be
described with a quantitative measurement. Quantitative
characteristics might include height, weight, and blood pressure in humans, growth rate in mice, seed weight in plants,
and milk production in cattle.
Quantitative characteristics arise from two phenomena.
First, many are polygenic: they are influenced by genes at
many loci. If many loci take part, many genotypes are possible, each producing a slightly different phenotype. Second,
quantitative characteristics often arise when environmental
factors affect the phenotype, because environmental differences result in a single genotype producing a range of phenotypes. Most continuously varying characteristics are both
polygenic and influenced by environmental factors, and
these characteristics are said to be multifactorial.
The Relation Between Genotype
Continuously and Many
Are Influenced by Alleles
at Multiple Loci
Qualitative, or discontinuous, characteristics possess only a
few distinct phenotypes (Figure 16.1a); these characteristics
are the types studied by Mendel and have been the focus of
our attention thus far. However, many characteristics vary
continuously along a scale of measurement with many overlapping phenotypes (Figure 16.1b). They are referred to as
For many discontinuous characteristics, the relation
between genotype and phenotype is straightforward. Each
genotype produces a single phenotype, and most phenotypes are encoded by a single genotype. Dominance and
epistasis may allow two or three genotypes to produce the
same phenotype, but the relation remains simple. This simple relation between genotype and phenotype allowed
Mendel to decipher the basic rules of inheritance from his
crosses with pea plants; it also permits us both to predict the
outcome of genetic crosses and to assign genotypes to
(a) Discontinuous characteristic
1 A discontinuous (qualitative)
characteristic exhibits only
a few, easily distinguished
2 The plants are either
dwarf or tall.
Number of individuals
all have one gene that encodes a plant hormone. These genotypes produce one dose of the hormone and a plant that is
11 cm tall. Even in this simple example of only three loci, the
relation between genotype and phenotype is quite complex.
The more loci encoding a characteristic, the greater the
The influence of environment on a characteristic also
can complicate the relation between genotype and
Hypothetical example of plant
height determined by pairs of
alleles at each of three loci
Doses of Hormone
(b) Continuous characteristic
4 The plants exhibit a
wide range of heights.
AϪAϪ BϪBϪ CϪCϪ
A A B B C C
A A B B C C
Number of individuals
3 A continuous (quantitative)
characteristic exhibits a
continuous range of
AϪAϪ BϪBϪ CϪCϩ
AϩAϩ BϪBϪ CϪCϪ
A A B B C C
AϪAϪ BϪBϪ CϩCϩ
AϩAϪ BϩBϪ CϪCϪ
AϩAϪ BϪBϪ CϩCϪ
AϪAϪ BϩBϪ CϩCϪ
AϩAϩ BϩBϪ CϪCϪ
16.1 Discontinuous and continuous characteristics differ in
A A B B C C
the number of phenotypes exhibited.
AϩAϪ BϩBϩ CϪCϪ
For quantitative characteristics, the relation between
genotype and phenotype is often more complex. If the characteristic is polygenic, many different genotypes are possible,
several of which may produce the same phenotype. For
instance, consider a plant whose height is determined by
three loci (A, B, and C), each of which has two alleles.
Assume that one allele at each locus (Aϩ, Bϩ, and Cϩ)
encodes a plant hormone that causes the plant to grow 1 cm
above its baseline height of 10 cm. The other allele at each
locus (AϪ, BϪ, and CϪ) does not encode a plant hormone
and thus does not contribute to additional height. If we consider only the two alleles at a single locus, 3 genotypes are
possible (AϩAϩ, AϩAϪ, and AϪAϪ). If all three loci are taken
into account, there are a total of 33 ϭ 27 possible multilocus
genotypes (AϩAϩ BϩBϩ CϩCϩ, AϩAϪ BϩBϩ CϩCϩ, etc.).
Although there are 27 genotypes, they produce only seven
phenotypes (10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, and
16 cm in height). Some of the genotypes produce the same
phenotype (Table 16.1); for example, genotypes AϩAϪ
BϪBϪ CϪCϪ, AϪAϪ BϩBϪ CϪCϪ, and AϪAϪ BϪBϪ CϩCϪ
AϪAϪ BϩBϩ CϩCϪ
AϩAϪ BϪBϪ CϩCϩ
AϪAϪ BϩBϪ CϩCϩ
AϩAϪ BϩBϪ CϩCϪ
AϩAϩ BϩBϩ CϪCϪ
A A B B C C
AϩAϪ BϩBϩ CϩCϪ
AϪAϪ BϩBϩ CϩCϩ
AϩAϩ BϪBϪ CϩCϩ
AϩAϪ BϩBϪ CϩCϩ
AϩAϩ BϩBϩ CϩCϪ
A A B B C C
AϩAϩ BϩBϪ CϩCϩ
AϩAϩ BϩBϩ CϩCϩ
Note: Each ϩ allele contributes 1 cm in height above a baseline of 10 cm.