St. Louis scientists, first to sequence a cancer genome, discuss how and why | St. Louis Public Radio

St. Louis scientists, first to sequence a cancer genome, discuss how and why

Nov 18, 2008

This article first appeared in the St. Louis Beacon: November 18, 2008 - In the world of cancer research, the patient is the unsung hero. Without patients and families willing to take part, much of genetic research into the origins of cancer would not be possible. With this partnership, scientists at Washington University in St. Louis are the first to sequence the complete genome of a tumor and compare it, side-by-side, with the genome of healthy cells from the same person. It is, they hope, a step toward personalized cancer treatment.

"We view the patients as our collaborators," said Timothy Ley, professor of medicine at Washington University in St. Louis and the study's director. "If the patients don't participate in these studies, we can't do anything."

Acute Myeloid Leukemia

In this landmark study, the patient had a blood cancer called acute myeloid leukemia. AML causes uncontrolled division of white blood cells. These abnormal white blood cells gather in the bone marrow and crowd out the production of normal and necessary cells, including red blood cells for oxygen transport and platelets for clotting.

Scientists don't know what causes this cancer. They don't know why some patients respond well to treatment, but others do not. This study, published in the Nov. 6 issue of Nature, does not solve these mysteries. But, in looking for solutions, it has shown that sequencing whole cancer genomes, and comparing them to normal counterparts, can uncover mutations that would have otherwise gone undiscovered.

A New Tool

Sequencing the whole human genome is no small task. This current study required sequencing two genomes - one from the patient's tumor and one from her healthy skin cells. In addition to being the first cancer patient to have her genome sequenced, she is also the first woman.

The slightly older DNA sequencing tools work well for looking at snap-shots of the genome -- pieces of it that scientists have a hunch might be involved with cancer. Sometimes the hunch is right, but many times, including with AML, they find nothing useful. According to Ley, this strategy is more difficult than searching for a needle in a haystack. "We weren't even sifting through the whole hay stack," he said. "We just took samples of it. We realized we were never going to get there without looking at the whole genome."

Fortunately, the last three to four years have seen the development of next-generation sequencing technology. Ley says this new method can sequence an entire genome both 100 times faster and 100 times cheaper than the current technologies. Called massively parallel sequencing technology, it was not developed by the Washington University scientists, but they are the first to use it to identify mutations leading to cancer.

"We've known for a couple of years that this new technology was coming down the pike," said Richard Wilson, director of the Genome Sequencing Center at Washington University and senior author of the study. "It allows us to step back and look at all 25,000 genes and the DNA that surrounds those genes, instead of just the usual suspects of cancer."

New Discoveries, Better Treatments

In this study, the normal skin cells and the tumor cells came from the same person. Therefore, any differences between the two sequences are likely to be the mutations causing the cancer. "Our greatest fear was that we would find 10,000 mutations -- so many that we would never know which ones were relevant," said Ley. "But instead we found 10."

With such a small number, the scientists speculate that all the mutations are probably important for the cancer. Of the 10 genetic mutations identified in the study, eight were previously unknown in AML. That they found nine of the mutations in nearly all the tumor cells further supports the idea that all of them are important to the cancerous nature of the cell. They propose that the one mutation that occurs less frequently is also the most recent.

Three of the eight newly discovered mutations were in genes that should work to prevent the growth of tumors. Conversely, four mutations may encourage the growth of cancer by, in one instance, mimicking the self-renewing properties of embryonic stem cells. And one mutation appeared to stop drug-delivery into the cell -- one possible reason that chemotherapy did not work well on this patient's cancer. In a surprising twist, these eight novel mutations were not found in any tumor samples from 187 other AML patients. "It means there are probably many combinations of mutations that can lead to this disease," said Ley.

Since this study shows that most of the mutations are unique to this patient, Ley suggests that it would be difficult to target individual genes with designer drugs. But, both Ley and Wilson see promise in targeting the pathways that are turned off or on by the mutations. For example, one drug could fix a pathway that suppresses tumors and a different drug could interfere with a pathway that helps tumors grow. If you can't turn the faucet off you can still put a kink in the hose. "It could be that there will be some Achilles heel for each of these pathways at some later point than where the individual genes are involved," Ley said.

Knowing the mutations of a patient's cancer can help improve treatment, even without newly designed drugs. For example, if the patient has a mutation that keeps a certain chemotherapy drug out of the cancer cells, the doctor will know not to prescribe that drug.

"Chemo drugs typically make people ill," said Wilson. "And if you're giving them something they don't need, you're making the situation worse."

The Next Step

Wilson called this study the tip of the iceberg and emphasized the leading role that Washington University has taken in this research as one of only three large genome centers in the United States. "The local angle is exciting. There are not many places in the world where this kind of thing can happen. This is the first application of this technology to cancer," he said. Now that the first cancer genome has been sequenced, the next step is to continue sequencing more individual genomes and to expand the research to other kinds of cancer.

"You need the whole genome to understand cancer," said Ley. "And it is our ultimate goal for all patients with cancer - to be able to do this cheaply enough and quickly enough so that you can have all the information to inform treatment decisions."

While this AML patient's contribution to science could not save her life, it offers hope and a blueprint for future therapy. "Most of the patients are not doing it for themselves. They're doing it for the people who come later," said Ley. "Our hats are off to them -- they're our inspiration."

Julia Evangelou Strait is a freelance science writer based in St. Louis. She has a master's degree in biomedical engineering and works in hospital epidemiology for BJC HealthCare.