Download LESSON 5.5 WORKBOOK How will cancer be treated in the 21st century?

LESSON 5.5 WORKBOOK
How will cancer be treated in the
21st century?
DEFINITIONS OF TERMS
Driver mutation – a mutation
in a proto-oncogene or tumor
suppressor gene that drives the
transformation of a normal cell
into a malignant cancer cell.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.5
We now understand that how cancer progresses and whether it responds to
chemotherapy is a product of the gene mutations it accumulates. Yet none of the
current treatment options (surgery, radiation, and chemotherapy) target cancer
cells based upon the types of mutations the cells have acquired. This lesson
focuses on the future of cancer treatment and in particular how the genetic
sequences of tumors can be used to determine which therapies will be effective
to treat individual cancers. A more personalized approach to treatment should be
more successful than the current ‘one size fits all’ treatments.
MC Questions:
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Current cancer treatment is a relic of the past
The past few lessons have described the commonly used conventional approaches to cancer treatment.
All of them — surgery, chemotherapy, and radiation therapy — focus on killing cells on the basis of their
location or their proliferation rate. Even in the 21st century cancer treatments that address the underlying
cause of cancer — specific DNA mutations — or use other approaches to killing cancer cells, such as
activating the immune system, are largely experimental.
One element crucial to cancer progression that has only recently been appreciated is the so-called driver
mutations. These mutations to specific parts of specific proteins allow cells to acquire specific traits useful
to take advantage of selection pressure that will kill unprepared cells. If a treatment like chemotherapy kills
rapidly dividing cells randomly then any cell surviving the treatment that has already acquired the ability to
form secondary tumors will have a selective advantage. The presence of driver mutations explains why
many cancers relapse after chemotherapy. The future of cancer treatment lies in the ability to selectively
kill cells that have acquired driver mutations. We are closer now than ever to this goal, thanks to advances
in DNA sequencing.
1. What is the biggest problem with
current treatments for cancer?
aa. They are very expensive;
bb. They are less effective for
metastatic cells;
cc. They do not kill slow-growing
cells;
dd. They cannot kill cells that have
driver mutations.
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LESSON READINGS
MC Questions:
Understanding cancer through deep sequencing
DEFINITIONS OF TERMS
Deep sequencing – a type of
DNA sequencing that uses computers to assemble of small DNA
sequences into a much longer
sequence, such as a genome.
Reference DNA – the DNA
sequence that is assembled
through the sequencing process.
Depth of Coverage – the number of sequence fragments that
overlap a given nucleotide during
a sequencing process
Wo r k b o o k
Lesson 5.5
Figure 1: Deep sequencing uses millions of short DNA sequences to assemble
much larger sequences, called the reference DNA, like as the genome. The short
regions of DNA are produced randomly and often overlap. Areas where many
sequences overlap have good coverage, while areas were few sequences overlap have
‘poor coverage’. Depth of coverage refers to how many times a single nucleotide is
represented in individual segments.
In 1987 a group of scientists proposed to collaborate to determine the exact sequence of nucleotides in
the entire human genome. These days, when we can find out our own genome sequences for only about
$1000 it is difficult to grasp how audacious the idea was at the time, and the technological advances
required for it to succeed. In 2001 the first draft of the genome sequence of one anonymous DNA donor
was published. (That donor is now known to be the famous biotechnologist Craig Venter). The human
genome-sequencing project would not have been possible without a number of new techniques that were
invented to sequence DNA faster and more efficiently. One of these techniques that has the potential to
revolutionize cancer treatment is called deep sequencing.
When the genome-sequencing project was begun, the only way to determine how nucleotides are
arranged in the genome was to chop up the DNA into segments 700-1000 bases in length and sequence
the segments individually. These sequences were then stitched together to build a reference DNA
sequence for the full genome. The method relied on specific enzymes that cut up the DNA at certain
points, and so it was effective only in areas where many of those enzymes could cut, so that there was
good overlap between segments (see Figure 1). But the enzymes didn’t work well in some areas of the
genome, which remained poorly sequenced for years. The development of more advanced computers that could handle large amounts of sequencing information at once changed the approach. Now
specific enzymes were not needed to cut the DNA. Instead it could be physically fractured into much
smaller pieces only 50-100 nucleotides long. The computers could then assemble millions of these
short sequences together to build a reference DNA sequence that covered the whole genome. The new
method, which randomly generates overlapping sequences increases the depth of coverage of the DNA
(see Figure 1) which is why it is called ‘deep’ sequencing.
2. What is deep sequencing?
aa. A type of sequencing of cells
deep within a tumor;
bb. A sequencing assembly using
DNA fragments of 50-100 bases;
cc. A sequencing assembly using
DNA fragments of 700-1000
bases;
dd. A type of sequencing of large
stretches of DNA.
3. What is the difference between good
coverage and poor coverage?
aa. Number of segments that cover
a given DNA nucleotide;
bb. Number of sequences that are
accurate for a segment of DNA;
cc. Number of DNA segments that
are covered by sequencing;
dd. None of the above.
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LESSON READINGS
DEFINITIONS OF TERMS
The Cancer Genome Atlas
(TCGA) – a project to sequence
the genomes of many different
cancers to identify the types of
mutations that develop.
Transcriptome – the set of all
the messenger RNA molecules
made in a cell.
Epigenetics – the study of how
modifications to the DNA that do
not affect DNA sequence affect
gene expression.
Epigenome – a record of all of
the chemical changes of histones
and DNA and where these
changes are present along the
genome
Germline mutation – any
detectable mutation or variation
of DNA present within germ cells.
Somatic mutation – a change in
DNA sequence of a somatic cell.
Wo r k b o o k
Lesson 5.5
As the computers that permitted deep sequencing became faster and more efficient the time and cost to
sequence an entire genome fell from the 11 years and $3 billion dollars it originally cost to sequence Craig
Venter’s DNA to a few weeks and merely $1000 (as of this writing in late 2014). As the cost of genetic
sequencing has gone down, it has made sense to expand our efforts away from understanding the
healthy genome to include understanding the genome in disease. The US government has funded a new
project to understand the genetic origins of cancer called The Cancer Genome Atlas (TCGA). The goal
of this project is to sequence the genome of clinically important cancers including brain, bladder, breast,
colorectal, head and neck, kidney, leukemia, melanoma, prostate, stomach, and thyroid cancers and then
to map the types of genetic changes that occur in various types of cancers thereby making an ‘atlas’ of
key mutations.
But as we have learned, the DNA sequence of the genome only provides partial information – it is more
important to know what proteins are being expressed in cancer cells and how mutations might have
changed their functions. Realizing this, TCGA also plans to sequence the full repertoire of the RNA
transcripts produced in cancer cells that will be translated into proteins. This is called the transcriptome
map. Sequencing and then mapping the RNA Transcriptome sequencing should be especially useful for
identifying which RNA splicing variants are only produced in certain cancers or for identifying novel genes
expressed in cancer because of gene fusion events.
Another area we have learned about
that we expect will become increasingly
important in expanding our understanding
of how cancer progresses lies in the field of
epigenetics. Remembering back to Unit 2,
epigenetics studies how DNA structure can
be modified to control how tightly it is folded
and hence when a gene will be expressed.
The importance of epigenetics is that
even though it doesn’t change a gene’s
sequence, its effects can be passed down
Figure 2: Webpage for the Cancer Genome
from generation to generation. We have
Atlas (http://cancergenome.nih.gov/ ) holds
very little understanding of how epigenetics
genome, transcriptome, and epigenome data
might affect cancer. The third part of the
for several types of cancers of several organs.
TCGA project is therefore to create an
epigenome map to determine which regions
of DNA structure are epigenetically modified
in different cancers. This knowledge may provide important information about cancer inheritance that
doesn’t depend on modifications to actual genome structure.
MC Questions:
4. True or False: The Cancer Genome
Atlas will examine the sequence of
multiple different types of cancers to
map common genetic changes.
aa. True.
bb. False.
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5. Which of the following is information
that will be acquired by the cancer
genome atlas? (Circle all correct.)
aa. Genome of cancers.
bb. mRNAs of cancers.
cc. Histones acetylated in cancers.
dd. Proteins made in cancer.
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LESSON READINGS
DNA sequencing and assessing cancer risk
In Unit 3 we learned about the difference between germline and somatic mutations. Germline mutations
occur in our germ cells (i.e. sperm cells for men, and egg cells for women), while somatic mutations
occur in any other cell in our body. We learned that germline mutations can be inherited, whereas somatic
mutations cannot. Germline mutations can be used to compare one person’s DNA to another, and, in
comparison with incidences of cancer, to assess which mutations may increase an individual’s risk for
developing incidences of cancer.
DEFINITIONS OF TERMS
Genetic screens – a type of
screen to identifies specific types
of mutations that may predispose
for cancer risk.
Prophylactic mastectomy
– surgery to remove one or both
breasts in order to reduce the risk
of developing breast cancer.
Wo r k b o o k
Lesson 5.5
Two well-known types of germline mutations that have definitively been associated with increased risk
of cancer are to the BRCA1 and BRCA2 tumor suppressor genes. Mutations to BRCA1 and BRCA2 are
most commonly associated with an increased risk of breast and ovarian cancer, but are also associated
with risk for colon, prostate, and pancreatic cancers. Other notable germline mutations linked to development of cancer include the Rb mutations that are associated with retinoblastoma (cancer of the retina)
and leukemia, and the p53 mutations that are associated with sarcomas, breast cancer, brain cancer, and
leukemia, as well as many other types of cancer.
The technology to perform genetic screens for germline mutations is readily available, people with family
histories of these types of cancer are recommended to be screened. In some cases the knowledge
gained from a positive screen can be used to prevent the cancers occurring. For example, the actress
Angelina Jolie recently announced that based on a family history of breast and ovarian cancer (her
mother died from ovarian cancer at a relatively young
age) she had been screened for BRCA1 and BRCA2
mutations. Based on a positive results she had undergone
a prophylactic mastectomy to remove both her breasts
even though she had not been diagnosed with cancer. Jolie
knew that the type of BRCA1 mutations she carried meant
that this surgery decreased her risk of breast cancer by
87%. However not all BRCA1 mutations confer the same
risk, and because of this prophylactic surgery is not the
answer for all people with BRCA1 or BRCA2 mutations. On
the other hand prophylactic breast surgery is not enough for
Figure 3: Angelina Jolie’s
women with the types of BRCA1 and BRCA2 mutations that
mutations in the BRCA 1
also significantly increase their risk of ovarian cancer. These
gene led to a prophylactic
women may also need to consider prophylactic removal of
mastectomy to reduce the risk
their ovaries. The ability to consider different options on a
of developing breast cancer.
case-by-case basis is an example of personalized medicine.
MC Questions:
6. True or False: Presence of BRCA1
is associated with increased risk of
breast and ovarian cancer.
aa. True.
bb. False.
7. What should decisions for cancer
treatment following a genetic screen
take into account? (Circle all correct.)
aa. An accurate assessment of the
risk of developing cancer.
bb. An accurate assessment of how
the treatment may affect the risk.
cc. An accurate assessment of the
dangers of the treatment relative
to the risk.
dd. All of the above.
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LESSON READINGS
However it is important to evaluate the options carefully with an understanding of what the risk means.
Undergoing prophylactic surgery when the risk does not warrant it is another example of overtreatment.
Only 5-10% of all cancers have been attributed to inheritance of germline mutations to DNA. More may
be inherited via epigenetic modifications, as we discussed above, but we have little understanding of
epigenetic factors at present. The remainder of cancers appear to arise spontaneously in somatic cells.
To develop treatments for these cancers we will need to understand how different cells acquire the mutations that drive them towards becoming malignant.
DEFINITIONS OF TERMS
Personalized medicine – a type
of treatment plan that involves
customization of therapy to
specific cancers.
DNA sequencing of cancers: personalized treatment
As genetic sequencing becomes cheaper and more available, information about which mutations are key
drivers in cancer progression is becoming much clearer, and this allows us to design a logical strategy for
treatment rather than the non-specific ‘slash, burn and poison’ approach we have been using.
■■ When and how driver mutations are acquired may be more important than the tissue the cancer
develops in: For example if a lung cancer and a pancreatic cancer have the same mutations it
makes more sense to treat them both with the same drug that inhibits the driver’s activity than to
treat them with different drugs that were developed without taking into consideration how the cells
are abnormal.
■■ It is important to understand when metastasis occurs. If certain driver mutation are associated with
metastasis it makes more sense to include a treatment (like chemotherapy) that can kill metastatic
cells early in the treatment, rather than just removing the primary tumor.
■■ Tumors acquire mutations randomly so we need to be careful of selective pressures allow a resistant
population to persist even if most cells in the tumor are killed. We need to be able to kill that population too.
Wo r k b o o k
Lesson 5.5
The understanding, that each tumor has its own individual characteristics has given rise to the notion of
personalized medicine. Personalized medicine will take into account any germline mutations (genetic
and epigenetic) as well as the somatic mutations within a cancer, as well as the gene expression within
the tumor to design a treatment plan for that specific individual. This treatment may involve harnessing
the body’s own ability to fight disease via the immune system. The treatment focus has now shifted from
finding the cure for cancer to finding the unique cure for each unique cancer. We are within reach of finally
being able to treat cancer as a disease of evolution. This is the future of cancer treatment in the 21st
century, and the final battle in the war on cancer.
MC Questions:
8. What major advance may be crucial
to the development of personalized
medicine for treating cancer in the
21st century? (Circle all correct.)
aa. Combinatorial chemotherapy.
bb. Deep Sequencing.
cc. Radiation therapy.
dd. The Cancer Genome Atlas.
9. Which of the following would be
taken into account when designing
a personalized medicine treatment?
(Circle all correct.)
aa. That person’s genomic
sequence.
bb. That person’s cancer DNA
sequence.
cc. That person’s transcriptome.
dd. That person’s cancer
transcriptome.
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STUDENT RESPONSES
Identify three challenges in treating cancer that current treatments do not address and explain how personalized medicine
could be used to address them.
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Remember to identify your
sources
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Wo r k b o o k
Lesson 5.5
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.5
DEFINITION
Deep sequencing
A type of DNA sequencing that uses computers to assemble of small DNA sequences into a much longer
sequence, such as a genome.
Depth of Coverage
The number of sequence fragments that overlap a given nucleotide during a sequencing process
Driver mutation
A mutation in a proto-oncogene or tumor suppressor gene that drives the transformation of a normal cell into
a malignant cancer cell.
Epigenetics
The study of how modifications to the DNA that do not affect DNA sequence affect gene expression.
Epigenome A record of all of the chemical changes of histones and DNA and where these changes are present along
the genome
Genetic screens
A type of screen to identifies specific types of mutations that may predispose for cancer risk.
Germline mutation
Any detectable mutation or variation of DNA present within germ cells.
Personalized medicine
A type of treatment plan that involves customization of therapy to specific cancers.
Prophylactic mastectomy
Surgery to remove one or both breasts in order to reduce the risk of developing breast cancer.
Reference DNA
The DNA sequence that is assembled through the sequencing process.
Somatic mutation
A change in DNA sequence of a somatic cell.
The Cancer Genome
Atlas (TCGA)
A project to sequence the genomes of many different cancers to identify the types of mutations that develop.
Transcriptome
The set of all the messenger RNA molecules made in a cell.
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