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Two-Hit Hypothesis and Genomic Instability

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Introduction to the Biology of Cancer

Johns Hopkins University

4.7 (2,062 ratings) | 80K Students Enrolled

Over 500,000 people in the United States and over 8 million people worldwide are dying every year from cancer. As people live longer, the incidence of cancer is rising worldwide and the disease is expected to strike over 20 million people annually by 2030. This open course is designed for people who would like to develop an understanding of cancer and how it is prevented, diagnosed, and treated. The course introduces the molecular biology of cancer (oncogenes and tumor suppressor genes) as well as the biologic hallmarks of cancer. The course also describes the risk factors for the major cancers worldwide, including lung cancer, breast cancer, colon cancer, prostate cancer, liver cancer, and stomach cancer. We explain how cancer is staged, the major ways cancer is found by imaging, and how the major cancers are treated. In addition to the core materials, this course includes two Honors lessons devoted to cancers of the liver and prostate. Upon successful completion of this course, you will be able to: - Identify the major types of cancer worldwide. (Lecture 1) - Describe how genes contribute to the risk and growth of cancer. (Lecture 2) - List and describe the ten cellular hallmarks of cancer. (Lecture 3) - Define metastasis, and identify the major steps in the metastatic process. (Lecture 4) - Describe the role of imaging in the screening, diagnosis, staging, and treatments of cancer. (Lecture 5) - Explain how cancer is treated. (Lecture 6) We hope that this course gives you a basic understanding of cancer biology and treatment. The course is not designed for patients seeking treatment guidance – but it can help you understand how cancer develops and provides a framework for understanding cancer diagnosis and treatment.

Skills You'll Learn

Cancer, Biology, Cancer Biology, Cancer Genetics

Reviews

4.7 (2,062 ratings)

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OK

Nov 23, 2016

It will be very helpful to me for doing my research work on the very same topic.\n\nBut all of these courses should be free of cost,just like this one.\n\nThanking you once again !\n\nRegards.

IY

Feb 25, 2017

great course with very experience lecturers . it has helped me to gain more insight into cancer development. thank you so much Dr. Kenneth J. Pienta and the other doctors. God bless you all.

From the lesson

Genetics of Cancer

Now, we'll turn our attention to the genetics of cancer, variation and mutation, two-hit hypothesis, and genomic instability.

Genetics Overview1:18

Basic Introduction to Genetics5:38

Genetic Variation and Mutation3:03

Two-Hit Hypothesis and Genomic Instability6:49

Taught By

Kenneth J. Pienta, M.D.
The Donald S. Coffey Professor of Urology

Transcript

Welcome back.

In this section, we'll be talking about Two-Hit Hypothesis and

Genomic Instability.

And really, where those mutations come from in the first place.

So you can acquire mutations two different ways,

either through somatic mutation or germide mutation.

Somatic mutations are acquired by somatic cells,

which are all the cells of the body, except eggs or

sperm and those mutations are passed on to daughter cells during cell proliferation.

It is important to remember that these mutations cannot be inherited by

offspring.

Every time a cell divides, it must replicate its DNA and

errors just get made by chance.

So, you'll remember what we talked about before with a lot of DNA

packed into a very small area.

So just by chance, about 1 mutation is made every 10 billion base pairs.

There is an increase in DNA damage and

subsequent replication error due to environmental carcinogens as well.

These include UV damage, which is also shown in the cartoon to

the right where an incoming UV photon hits the DNA and damages it.

So that it causes nics in the DNA which you can see to the far right, which then

have to be repaired by the cell and this can cause an increase risk to skin cancer.

Similarly, smoking causes chemical damage to lung cells and hepatitis and

alcohol abuse can lead to damaging cirrhosis of liver cells.

You might remember these from another lecture that where Dr.

Pienta discussed the risks to different cancers.

The other way you can get mutations is by inheriting them and

these are called germline mutations or inherited mutations.

In these mutations are present in the germ cell.

So in this case, that's the egg or the sperm and are inherited by offspring.

So, it's just the genetic variation that we're born with.

Germline variation accounts for why offspring look similar to, but

not identical to their parents.

When cancer is said to run in families, it may be due to these inherited mutations.

For example, women who inherit a BRCA 1/2 mutation are at increased risk for

breast cancer.

And individuals who inherit a CDH1 mutation are at increased risk for

stomach cancer, but

not all women who inherit a BRCA1/2 mutation develop breast cancer.

How does that work?

This is where it becomes important to remember that cancer is caused by

an accumulation of detrimental variation in the genome.

The biggest risk factor for developing cancer is aging.

Over time, we accumulate mutations and

this either happens by random replication error or by increase

replication error due to carcinogens that cause DNA damage as we discussed before.

The Two-Hit Hypothesis describes why not all

women with a BRCA1/2 mutation get breast cancer.

You'll remember that humans are diploid.

We have two copies of every gene.

One maternal, one paternal.

This means that even if one copy of a gene or allele is mutated,

the other copy can allow the protein to operate normally.

In order for a gene to be cancer inducing, both copies of the gene must be affected.

The second so-called hit may alter the DNA directly via mutation or

it may alter the expression of the DNA, the epigenetic mechanism.

So let's talk through an example of this, we'll work through the top tree first.

On the far left, you can see a parent who with his partner pass on

two normal copies of a gene to their child.

Over the lifetime of this individual,

he accumulates mutations including one hit in the gene shown here.

Importantly, the other copy of the gene that was normal

that did not have a mutation allowed it to be expressed normally.

Eventually, however, this individual acquired another mutation in the same gene

and this resulted in the gene becoming a cancer causing genetic mutant.

In the bottom example where you see an example of inherited or

germline mutation causing increased risk to an individual over a lifetime.

In this case, the parents passed on one mutated copy of the gene and

one normal copy of the gene.

In this case, as the individual progresses thru life,

he only needs one additional head in order for the gene to be cancer causing.

Most cancer requires mutations and multiple different types of genes.

In order to survive, a cancer cell must overcome normal regulation of

self-proliferation, cell survival and cellular communication in other so-called

hall marks of cancer that will be discussed by Dr. Sarif in a later lecture.

Each of these processes are tightly regulated in a normal cells by multiple

redundant pathways.

This means then in order to become cancerous,

a cell must accumulate mutations in multiple of these pathways.

It's been described as usually a minimum of six to seven

in multiple different genes.

So, you can see an example of this to the far right.

At the top, we see a normal cell where a mutation is inactivated a tumor

suppressor gene, so we see increased proliferation.

This cell doesn't become malignant yet, though.

First, it undergoes mutation that inactivates DNA repair genes.

And additionally, mutation that activates an oncogene and

then mutations that inactivate several different tumor suppressor genes,

that then induce it to become cancer.

In addition, cancer cells show a great deal of genomic instability.

In genomic instability describes how cells can survive and

divide with higher rates of mutation than in normal cells.

So in a normal cell, DNA replication error results in programmed cell death or

apoptosis, which you can see in the lighter color box over to your right.

And a cancer cell that same DNA replication error with the same DNA

replication error cells continue to divide and

pass that mutation on to daughter cells.

Over time, these mutations and this repair pathways will accumulate.

Some cells never undergo that program cell death

in the frequency of mutation in the cancer cell genome increases.

This increase in mutation rate leads to tumor cell heterogeneity and

that's one of the reason why cancer patients become resistant to treatment.

This brings us to the end of our lecture.

I hope this gave you a good understanding of the basics of genetics in order to

better understand the rest of this lecture series and introduction of cancer biology.

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