By Dr. Thomas J. Hudson  » Recently, I had the opportunity to visit Vaughan to speak at a fund-raiser for colorectal cancer research. As a scientist, it’s always a pleasure to visit communities and speak about the promising developments in cancer research. It’s also a pleasure to tell people that some of the most important cancer research is taking place right here in Ontario. 

In that spirit, I’d like to explain how my own research on colorectal cancer fits into the bigger picture of using the human genome to prevent, diagnose and treat cancer.

But first, what exactly is a genome and why is it so important to cancer?

The word “genome” comes from the words “genes” and “chromosomes” and refers to the entire genetic information that we inherit from our parents and transmit to our children. The genes and chromosomes that are part of everyone’s genome are present in all of the cells in our body. 

Our genes and chromosomes are made of DNA, which are large molecules arranged in a specific order that “spells out” the genetic code to make proteins, cells and organs, and keep these functioning from early-stage embryos to adulthood. Just as there are genes that contain the information needed to create bones or determine physical traits like hair colour, there are some genes which influence our risk for developing diseases like cancer. 

Humans have 46 chromosomes (two copies of chromosomes 1-22, plus two X chromosomes in women or an X and Y chromosome in men). In 2000, scientists from many countries released a draft sequence describing most of the human genetic code, a discovery that has profound implications for science. As you might remember, the Human Genome Project also caught the media’s attention, mainly for the many possibilities it offered for finding new ways to diagnose and treat disease.

As a leader of the team that created a high resolution map of the human genome in the mid 1990s, I was very proud of our accomplishment. But as a medical doctor, I also understood there was a lot more that needed to be done before I could use our new knowledge to prevent, diagnose and treat diseases in the clinic. Like everyone involved with the Human Genome Project, I was very interested in doing this “translational” work as quickly as possible. 

A first task was to develop an approach to track the variation that exists in the genomes of different people. Along with teams in Montreal, Toronto and Boston, my group developed key concepts that led to the creation of the International HapMap Consortium. The HapMap resource and technologies have led to the discovery of approximately 200 “common” disease genes in the last two years, such as asthma, heart disease, multiple sclerosis and cancer. 

Cancer is the leading cause of death in Canada. Genetic studies of cancer are difficult, because most cancers are not caused by a single “cancer gene” but by interactions between several genes and environmental factors such as tobacco, radiation and viruses. Although two cases of cancer may look very similar, they may actually have different genetic causes. 

Making matters even more complicated, there is a great deal of natural genetic variation in our genomes that appears to have no medical consequences. If we compare the genes of one patient who has cancer with one healthy individual, we would find a lot of variation, but this does not tell us which of those variations actually predispose to cancer (or prevent healthy individuals from getting cancer).

Five years ago, my colleagues at Cancer Care Ontario and Mount Sinai Hospital and my team at McGill University initiated a genome study of colorectal cancer called the ARCTIC project (ARCTIC stands for “Assessment of Risk for Colorectal Tumours in Canada”). The project involved testing 600,000 genetic markers that cover all human chromosomes, in 1,200 Ontarians who have had colon cancer, and 1,200 Ontarians who do not have colon cancer. This study, which involved over one billion genetic tests, was the first time the new “HapMap” tools were used in colon cancer research. 

In August 2007, we announced the discovery of the first genetic marker that predicts colon cancer. This marker is located on chromosome 8. Since then, our international colleagues and the ARCTIC team have identified 10 such markers (and we expect more to be found in the next few years). We now know that some individuals in the population carry just a few risk markers, while others carry many. Risk to colon cancer is now understood to depend on disease gene “dosage”. 

We are at the point of being able to classify individuals as having “high”, “medium” and “low” risk. In the next decade, we anticipate developing a blood test that will be used to predict risk of colorectal tumours in healthy individuals, and propose guidelines for early detection in high risk individuals.

For many reasons, the “revolution” of personalized medicine and genomics will not take place at once, but rather in gradual steps like screening tests that detect cancer earlier and improvements to treatments for specific cancer subtypes. 

Most people barely noticed the widespread introduction of new, scientific methods for curing disease around the turn of the last century, or the revolutionary impact of computers in medical research starting in the 1980s. So it’s likely that most people will not notice the gradual introduction of new, personalized diagnostic tools and treatments. But there is every reason to believe that over time, we will see a dramatic impact.

Genome research offers new opportunities to understand and treat cancer. The studies I’ve mentioned so far were about testing DNA in normal cells. However, we are also studying the DNA in cancer cells. This research has revealed that cancer cells contain thousands of DNA mutations that arose in the tumours themselves. Some of these mutations create new proteins or alter the quantity of certain proteins, which makes the cells very different than all other cells in the human body. 

While these mutations can have dramatic effects, such as the rapid growth and spread of cancer cells, we also are now seeing an opportunity to develop specific drugs which inactivate these cancer proteins. Early examples of these new drugs, such as Herceptin for a subtype of breast cancer, Iressa for a subtype of lung cancer, and Gleevac for a subtype of blood cancer have been very successful in stopping the growth of specific types of cancer cells, with very few side effects compared to traditional chemotherapies.

Over the last two years, it has become possible to contemplate a systematic study of cancer genomes, to find more cancer mutations that could be “druggable”. With this in mind, I recruited several top genome scientists from other US Genome Centres, and launched a massive genome study of pancreatic cancer. In parallel to this, I was asked by international funding agencies to coordinate the launch of similar projects. 

Since we announced the policies and guidelines of the International Cancer Genome Consortium in April 2008, government agencies and foundations in 10 countries have announced similar projects. Together, we have initiated projects targeting oral, breast, skin (melanoma), liver, stomach, blood, and other forms of cancers. Additional types of cancer will be included. 

Because each project will look at more than 500 tumours, and genomes are large (three billion DNA letters) each project requires more than $20 million. Over the next decade, we hope to launch studies for 50 types of cancer that affect people around the world at a total cost of $1 billion. The consortium will sequence 25,000 genomes, which is 25,000 times the size of the Human Genome Project (which also cost $1 billion). 

Fortunately, genome technologies have advanced. They are now incredibly fast and have become relatively inexpensive compared to the approaches used by the Human Genome Project.

I am very fortunate to lead the Ontario Institute for Cancer Research (OICR). The institute is bringing together some of the brightest minds in the province to collaborate on cancer research. 

Our approaches are not limited to genomics. We have world-class imaging groups developing innovative detection screens to see very small tumours (the One Millimetre Cancer Challenge), targeting cancer-initiating cells called Cancer Stem Cells, developing new drugs (in partnership with the Terry Fox Research Institute), testing new cancer drugs in our High Content Clinical Trials Program, and studying health care services (including health issues specific to cancer survivors). 

The institute receives staunch support from the Ontario government, through the Ministry of Research and Innovation, at a level which probably surpasses that of any provincial or state government in North America.

To help make the connections between environmental factors and cancer and other diseases, we are planning a large-scale population study called the Ontario Chronic Disease Cohort. This study will track people over decades to uncover which lifestyle factors are associated with which types of cancer. 

Unfortunately, unlike other research areas that can be accelerated through advances in technology, there is no way to speed up a cohort study; we must be patient and wait for our study population to age. Nonetheless, this is important research to understand the “environmental” factors in the daily lives of Ontarians that increase cancer risk. (When scientists use the term “environmental”, they’re talking about something much broader than what most people think. In addition to tobacco, which we already know is a major carcinogen, our lifestyle choices such as exercise and diet also impact the risk for many types of cancers).

Do we need to wait for new research or is there something already being done in Ontario that has an impact on cancer? In Ontario, the government already recommends adults over 50 get screened for colorectal cancer. This is a very important recommendation, because colorectal cancer is very difficult to treat if it is detected late. Through a program called ColonCancerCheck, Cancer Care Ontario is aiming to screen all Ontario adults over age 50 every two years. 

The first stage of screening is a fecal occult blood test (FOBT) that involves taking a sample at home and mailing it to a laboratory, which performs a highly sensitive test for traces of blood in the feces. This test cannot detect cancer by itself, but a positive result indicates someone has a higher likelihood of having cancer and should receive a diagnostic colonoscopy.

The FOBT is quick and non-invasive, but many people avoid it because they feel that fecal tests are yucky, or because they are not interested in follow-up tests such as colonoscopies. Tragically, many of the deaths from colorectal cancer each year could be prevented through screening. 

Cancer research is a lengthy and complicated process, and even projects like the colorectal blood test based on the ARCTIC project take several years to go from the laboratory to the clinic. In the meantime, we need to remember there’s a lot we can do right now, such as talking to a doctor about screening and avoiding well-known lifestyle risks like tobacco.

In the long run, however, research does pay off. Many of the best anti-cancer drugs were not around a generation ago. Advances in imaging have made radiation therapy more effective and surgery more accurate. Looking at it another way, the majority of children who are diagnosed with cancer today will live to see adulthood. The same thing could not be said 30 years ago.

I’ve touched on some of the reasons why we should be equally hopeful for the future. The human genome gives us a new level of knowledge about ourselves, and advances in sequencing technologies let us do wide-scale studies that would have been impossible just five years ago. 

Meanwhile, Ontario’s investment in translational research will make it possible to turn basic discoveries into diagnostic tools and new treatments quickly. Finally, greater knowledge of the environmental factors will shed light on how to control and manage cancer risk. 

This is a grand vision, and one that requires a great deal of dedication, investment and collaborative spirit. Cancer researchers do not work in isolation. Public participation is essential, from participation in population studies (such as the Ontario Chronic Diseases Cohort) and clinical research to funding of research from government, charitable donations, walk-a-thons, etc. The great news is that Ontario has outstanding researchers, a supportive government and a generous population.

• Thomas J. Hudson, MD, PhD is President and Scientific Director of the Ontario Institute for Cancer Research. This article first appeared in Whatever Magazine. To learn more about the Ontario Institute for Cancer Research, visit www.oicr.on.ca. To learn more about colorectal cancer screening and prevention, visit the Ontario government’s ColonCancerCheck site, www.coloncancercheck.ca.