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Feature Story: Sequencing the Big C

Cancer Cells

Sequencing the Big C

Elaine Mardis helped invent genome sequencing technology. Now she's bringing it to a group of people who really need it: cancer patients.

It had started with a few innocuous-seeming symptoms – a sore throat, a sudden tendency to bruise – but by the time the woman arrived at the hospital at Washington University in St. Louis, her prognosis was grim. Doctors biopsied her bone marrow and found it entirely overtaken by acute myeloid leukemia, an often fatal cancer of white blood cells. Three chemotherapy drugs and a stem-cell transplant – a regimen that far outstripped the standard of care – briefly cured her. But she soon relapsed. The doctors tried eight more drugs, irradiation, another stem-cell transplant. Nothing worked. Two years after diagnosis, the patient died. It was too late for her when Elaine Mardis and her colleagues at the university’s Genome Institute came in.

she compared the DNA samples letter by letter, and saw something unexpected – and the second part of the patient’s story began.

Elaine MardisMardis had spent most of her career developing technology to sequence genomes, and she wanted to know whether that technology could help in understanding and ultimately treating cancer. It was too late for this patient, but perhaps not for others. Mardis took samples of DNA from the patient’s cancer cells and from healthy skin tissue and sequenced the DNA of each in full. (Unlike the doctors who famously took tissue from Henrietta Lacks, she did so with the consent of the patient, who had enrolled on a research study for AML.) Then she compared the DNA samples letter by letter, and saw something unexpected – and the second part of the patient’s story began.  

Scientists have known for more than a century that cancer is a disease in which an otherwise normal cell’s genes go awry. Over the decades they have found many genes and proteins involved in that process. But only in the last five years have they had the technology to probe cancerous cells’ genomes in full and compare the results to those of healthy cells in fine detail. “There are lots of ways genes can be altered” for causing the onset of cancer, says Mardis, “and only with whole-genome methods can you pick many of them up.”

The results have yielded an astonishing panoply of ways that various types of cancer can scramble the DNA

scientist working at a sequencerSequencing the leukemia patient’s cancer cells revealed two mutations that scientists expected to see (they had been found before with less comprehensive techniques), and eight that no one had previously connected to leukemia. That was five years ago. Since then, scientists have sequenced many thousands of genomes from cancer patients. The results have yielded an astonishing panoply of ways that various types of cancer can scramble the DNA. They have demonstrated that what might be popularly thought of as a single disease – say, breast cancer – is in fact several different subtypes characterized by long lists of mostly different mutated genes. And they have both confirmed the importance of some previously suspected biochemical pathways in cancer and pointed toward new ones, such as cell metabolism and specific types of epigenetic regulation.

Sequencing has also demonstrated that each patient’s cancer cells may carry different combinations of mutations, a phenomenon called “genomic heterogeneity” that may help explain why some patients respond poorly to treatment. That was another surprise Mardis found in the leukemia patient. Many doctors had long believed that leukemia was a relatively simple disease typically involving just one “subclone,” or cancer genome. But this patient was carrying four. (Mardis and colleagues published those results last year.) One of the subclones had lurked in her bone marrow at low levels until the first round of chemotherapy treatment wiped out the others. Then, the remaining subclone acquired new mutations and took the others’ place, dooming the patient to relapse. Sequencing such heterogeneous cancers could help scientists to model and understand tumor behavior more accurately. It could also help in the clinic by indicating combinations of drugs or other treatments that offer a better chance of killing all present subclones, either in one shot or over time.

about a fifth of AML patients do not respond to first-line chemotherapy at all. “Quite frankly, we don’t understand why that is,” says Mardis

Sequencing could help patients in several other ways. First, it could be used to research the reasons that about a fifth of AML patients do not respond to first-line chemotherapy at all. “Quite frankly, we don’t understand why that is,” says Mardis. “But we might be able to use information from sequencing to identify additional targets or drugs that could get them into remission.” The other four-fifths of patients might benefit later, during relapse. Secondary rounds of tumor sequencing – possible now that the cost has fallen dramatically – could point to new mutations acquired by their cancer cells, thus suggesting further treatments.

green matrix of genome codeBut of course, sequencing does have limitations. As sensitive as it is, it still allows some variants, and thus some subclones, to fly under the radar. (Scientists can increase the technique’s sensitivity, but that raises the risk of false-positive results.) And researchers cannot yet easily distinguish between mutations that are driving the cancer process versus those that are essentially artifacts of that process, without doing additional experiments once they have been identified.

Analyzing sequence data also takes time – going from sample to full analysis takes at least six to eight weeks – and money. Mardis says the ideal clinical workup would include not just a whole genome sequence, but also a separate readout of the protein-coding genes (the exome) and another of all associated RNA molecules (the transcriptome). That costs upwards of $30,000 a patient. It’s still cheaper than many anti-cancer drugs. But for now, insurers generally don’t cover it because “they don’t think there’s enough data to support it yet,” says Eric Green, director of the National Human Genome Research Institute.

They are not the only skeptics. Many scientists prefer to pursue cancer research through smaller-scale methods such as focusing on single genes. Others say that, in a sense, genomics is not big enough – that to fully understand cancer, scientists need to elucidate not just genomic changes but their downstream effects on proteins, biochemical signaling, and the other processes that make up the life of the cell (and the tissue, and the person). Mardis is actually among these. She notes that cancer genomics was never meant to exist in isolation, and that the data must now be used to unravel “pathways and signaling mechanisms, the ways these variants ultimately interact to produce or regulate proteins that go on to affect each tissue.” To make that happen, scientists who work on all the relevant problems, at all scales, will have to work together instead of squabbling, she says. “It’s important to remember who we’re ultimately doing this for,” she adds, “and that’s the patients.”

Mary Carmichael is a science writer based in Boston, Massachusetts


(1) Next Generation Sequencing in the Clinic: A Perspective from Dr. Elaine Mardis. Integrated DNA Technologies.

(2) DNA Sequencing Lays Foundation for Personalized Cancer Treatment. The Genome Institute at Washington University.