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Promise and Progress - Sequencing Our Genes: Is Cancer Written in Our DNA?

Special Commemorative Issue of Promise & Progress: The Ludwig Center at Johns Hopkins

Sequencing Our Genes: Is Cancer Written in Our DNA?

By: Valerie Matthews-Mehl
Date: January 2, 2014

Dr. Bert Vogelstein Answers

Ken and Bert
1 2
Ken Kinzler, Ph.D. and Bert Vogelstein, M.D.

There is no one better suited to explain the intricacies of cancer genetics than Dr. Bert Vogelstein.  Dr. Vogelstein ranks today, as he has for more than a decade, as the preeminent international scientist.  His more than three decades of discoveries, revealing cancer as a genetic disease, are universally regarded as the most relevant in the field of cancer.  

He also is one of the world’s leading experts on a new technology called next-generation sequencing.  His laboratory has used it to scour the genome of the cancer cell and uncover the collection of genetic errors that make cancers originate, grow, and finally spread.

This technology also can be used to reveal an individual’s complete and entire DNA (whole genome).  Right now, it costs about $5,000 to sequence an individual’s whole genome, but the price tag is decreasing rapidly. With its increasing affordability, many have suggested that it could be used to identify individuals who were likely to develop cancer in the future as well as those who would be safe from the disease.  Dr. Vogelstein explains what the genome is, what whole genome sequencing can tell us about cancer risk, and as important, what it does not tell.

What is the whole genome and what does it tell us about cancer?

Our whole genome is the DNA we’re born with. For some of us that DNA contains the code for cancers that occur in our families.  These cancers are directly attributable to inherited genetic alterations. In this scenario, whole genome sequencing can be extremely beneficial in identifying the specific gene and mutation that is causing these cancers and potentially in determining how best to treat them.

However, most cancer is not related to an inherited genetic mutation. Most cancers develop in people with no hereditary predisposition. For the majority of the population, who were not born with a cancer-promoting alteration in their DNA, whole genome sequencing won’t predict whether they will get cancer. The reason is that our inherited DNA is not the final manuscript of our life and all of the health events we will face. Each of us plays an important part in editing and interpreting the script with the foods we eat, the air we breathe, and the habits we acquire. Other things, like random mistakes that cells make as they divide, also play a role but are out of our control.

In fact, heredity accounts for only about one percent of cancers.  For most people, lifestyle behaviors are far more damaging.  People cannot change the genes they inherit, but they can change behaviors. It is estimated that diet, obesity, and lack of exercise contribute to 35 percent of cancers, and smoking is a factor in an additional 30 percent of cancers.

Will whole genome sequencing predict cancer?

As the technology that makes it possible to quickly sequence an individual’s whole genome becomes increasingly more available and affordable, people have begun to wonder about its ability to predict diseases a person is likely to develop.  “If I had my whole genome sequenced, could it reveal whether or not I will develop cancer in the future?”

For this we turned to a database of 53,666 identical twins.  Twins are natural clones, and as such, they share the same genome.  Generally speaking, if one twin is followed over a period of time and all of the diseases he or she develops are cataloged and then compared to the other twin, measuring how often he or she developed the same diseases, it is possible to calculate inherited genetic risk for these diseases.

What many overlook in whole genome sequencing, particularly as it relates to cancer, is not about what it reveals, but rather what it does not.  

Ovarian cancer is a perfect example.  Our study predicted that about two percent of women who would undergo whole genome sequencing would get a positive result and alert them to an inherited genetic risk for ovarian cancer.  On the other hand, 98 percent of women would get a negative test result. That doesn’t mean these women won’t get cancer—based on ovarian cancer incidence rates, evidence proves that many of them will.  It just means that whole genome sequencing usually cannot predict which ones will develop the cancer and which ones will not. 

It also can be looked at in another way.  There are 156 million women in the United States today.  Based on current ovarian cancer rates, about 2.2 million of them will develop ovarian cancer sometime in their lives.  Whole genome sequencing could, with much further research, identify about 100,000 to 500,000 of them.  Most women—1.7 to 2.1 million of them—would have no sign of their impending cancers.

Where does that leave us then?

These calculations show that many individuals may indeed derive benefit from genetic tests for predisposition to cancers.  If the genetic information from these tests is provided to patients in a highly responsible manner, such testing could be useful and save lives.  On the other hand, most individuals who develop cancers will not be alerted to the fact that they will develop cancers.   In most cases, cancers do not result from hereditary factors but rather from environmental influences and bad luck.  The best way to manage cancer risk is through prevention and early detection.

People are rarely born with a cancer-causing genetic alteration.  Cancer is usually the result of accumulating edits made to the DNA of certain cells.  It would be a good idea, then, to eliminate as much as possible from our lives those things we know make these cancer-starting edits to cell DNA. According to cancer prevention experts, if we do just these things—applying the science we understand today to strengthen cancer prevention—we could decrease cancer incidence by half.

What about the cancer genome?

Just as every person is genetically unique, so is every cancer. While cancer is not usually written in the DNA we are born with, the story of each individual cancer is contained within the unique and different DNA of the cancer cell—the cancer genome rather than the genome people are born with. The cancer genome reveals the genetic alterations specific to each person’s cancer, and these alterations can be targeted to detect cancers, monitor them, and treat them.

Within a few years, we anticipate that all cancer patients at the Kimmel Cancer Center will have their tumors sequenced to reveal their cancer genomes. It will not only help cancer experts determine which treatments may work for a particular patient, but just as important, which ones may not.  This is the focus of personalized cancer medicine, and we have just begun to realize its potential.

Will cancer genome sequencing improve cancer prevention and treatment?

As tumor cells divide, they develop their own blood supply to get the nutrients they need to nourish and grow, and as a result, pieces of the cancer’s DNA get carried into the bloodstream, leaving telltale evidence of its existence.  In the Ludwig Center, our research team has developed a simple blood test that can detect DNA from cancer cells.  These tests have the potential to detect cancers before they are seen on X-rays, CT scans, or through other types of diagnostic methods and long before they cause symptoms. Universal, precise, and specific, this test can pluck one cancer cell from a sea of a half-million normal cells.  It can also help doctors determine whether a cancer therapy is working by measuring the amount of cancer DNA in the blood.  If a treatment is working, the amount of DNA should decline.  If it goes up, it’s a sign that the treatment may not be killing the cancer.   Rising levels of cancer DNA could also alert doctors that a cancer has come back.

Such a test, used together with the prevention strategies already discussed, could eventually make 75 percent of cancers curable.

Articles in this Issue

Directors Letter

Daniel K. Ludwig

Feature Story: The Gene Team

Honors & Awards

The Ludwig Center at Johns Hopkins

Headline Makers

Training Scientists Who Lead Cancer Discovery Around the Globe

Sequencing Our Genes: Is Cancer Written in Our DNA?

Ken Kinzler on the Ludwig Center