Genomic sequencing 101

Nearly every cell in the human body, from the ones in the fingernails to the ones deep inside the brain, contains a complete set of DNA, the operating instructions that influence everything from a person's hair color to susceptibility to disease.

For years, doctors have been able to test specific genes to detect the presence of mutations associated with disorders such as cystic fibrosis and sickle cell disease.

But only recently have scientists been able to map out a person's entire genetic code, or genome, by sequencing all 25,000 or so genes in one fell swoop.

How many have the potential to cause cancer? Dr. Stephen Ethier, chairman of breast cancer research at the Medical University of South Carolina says, "We're still searching for the final answer, but it's probably a few hundred genes. Some we know well. Most we still don't."

To sequence a person's genome, doctors need to collect less than a teaspoon of blood or saliva. Then chemicals are used from this sample to break open the cell membranes and gather the DNA that had been housed inside them. Enzymes strip away surrounding proteins to isolate a clump of tiny, whitish strands of DNA. That genetic material is placed in sophisticated machines that "read" each of the 3 billion base pairs that make up a person's genetic code.

Sequencing a genome used to take a year. Now, it can be done in a day.

Air Force veteran Charles Fitch is alive today, most likely because of "personalized" cancer treatment that used to be the stuff of science fiction, all thanks to cancer research and treatment based on genomics.

Genes vs. genome

In discussions about genetic testing, the terms "genes" and "genome" often get tossed around interchangeably. But they aren't the same thing.

Genes are inheritable information stored in a molecule of DNA. Humans have many thousands of genes, spaced across the entire set of DNA, which is packaged into 23 pairs of chromosomes.

A genome encompasses a person's entire set of genetic information across all 23 chromosome pairs, including all genes, gene-modifying sequences and everything in-between.

In regards to medicine, genomics basically refers to the analysis of an individual's complete set of DNA, or genome, and how to treat diseases based on the mutations or other changes that have occurred to genes in the sequence.

Fitch, a 53-year-old grandfather who lives in Mount Pleasant, was diagnosed with acute lymphoblastic leukemia in June 2011, a few weeks after he started having chest pains. Lab results showed that he had a low, and later plummeting, level of platelets in his blood.

After he was admitted to the Medical University of South Carolina's Hollings Cancer Center, genomic sequencing of Fitch's DNA showed he tested positive for the "Philadelphia chromosome," a specific chromosomal abnormality that is associated with chronic myelogenous leukemia, as well as 25 to 30 percent of the adults with acute lymphoblastic leukemia.

"This type of ALL is almost always fatal," says Dr. Robert Stuart, a hematologist at Hollings.

Starting from diagnosis, Stuart says the cancer team used Fitch's genomic information to determine a treatment regimen and to monitor progress. It even detected a relapse in August 2013 that would have otherwise not been "clinically apparent" and led to earlier intervention.

Today, Fitch is in remission, enjoying time with his family, activities from working out, cycling and paddling with Dragonboat Charleston, and has hopes to return to work on some level in a few years.

The future is here, now

Since the mapping of the human genome in 2003, genomics research has accelerated and is revolutionizing the approaches for prevention and treatment of diseases, including cancer.

And genomics is helping researchers understand how genes interact with nongenetic factors, such as diet, exercise and smoking.

Genomics research for medicine is happening in all disease fields and, in cancer, an estimated 50 to 100 researchers are actively engaged in it at MUSC, according to Stephen Ethier, chairman of breast cancer research.

"Genomics is going to change everything," says Ethier. "I'm doing things now that I never dreamed I could do when I was training to do this. And we are all having to continue to learn on the fly because it changes month to month and year to year."

Ethier came to MUSC two and half years ago as part of a strategic plan to improve and develop genomics research on campus.

"When I arrived here, my charge was to really get this moving forward, which meant a lot of different things. It meant developing state-of-the-art genomics sequencing technology on campus, which can be used both in a research setting and a clinical setting," says Ethier.

The first step was to begin to build the technical infrastructure for genomics sequencing, such as the recent purchase of sequencing instrument, an Illumina HiSeq2500, that costs a whopping $650,000.

"It can fit on a table and costs more than my house," says Ethier, noting that MUSC has invested nearly $2 million on the technology since he arrived.

At the same time, Ethier says MUSC has been recruiting scientists to do genomics research, including the relatively new chairman of the pathology department, Dr. Steven Carroll.

"Now we have state-of-the-art genomics sequencing technology that's in the genomics research lab, fully staffed with really outstanding people who are working with scientists all over campus to enhance the ability to do genomics research, not only in cancer, but in cardiology, pediatrics, neurology and immunology and so forth."

He adds that the sequencing work is good for both research and clinical work, the latter of which must be performed that meets the standards of the Clinical Laboratory Improvement Amendments, or CLIA.

"It's really been an exciting time. We've enhanced our ability technically and scientifically and put this stuff in place clinically as well," says Ethier.

End of chemo?

The latest mainstream news in cancer genomic breakthroughs came in late May when the Journal of American Medical Association published a study on genomic clinical trial that identified 10 "switches," or oncogenes, in two-thirds of lung cancer patients.

Those patients were given drugs that turned off those switches, instead of chemotherapy. Those given the molecular-targeted therapy lived about a year longer than patients treated more conventionally.

While some national news organizations called the finding "the beginning of the end for chemotherapy as the standard of care," MUSC's Ethier says not so fast.

"We're not close to making chemotherapy go away, but that's certainly a goal," says Ethier.

"We are in the middle now of this enormous shift in how cancer medicine has been practiced. For 50 years, cancer medicine was practiced one way. A patient would have a cancer diagnosis. A pathologist would look at those cancer cells under a microscope and would make a diagnosis based on his or her eyes and experience in training."

Treatments based on "tissue of origin," rather than individual genomics, typically are the same, says Ethier.

But he adds those regimens are "toxic and make people sick."

"The whole game of clinical oncology traditionally has been that we're going to give these drugs that are pretty toxic and we give them because they are more toxic to cancer cells than normal cells, but only by a little. The game played in the clinic is to deliver as much as these drugs as possible without killing the patient," says Ethier.

Genomics is changing the game.

"We now know very clearly that cancer is a genomic disease, not a genetic disease. It's not heritable from parent to children. It's not genetic, it's genomic. The cancer cells themselves acquire specific kinds of mutations in specific genes and when those mutations occur, those cancer cells begin to behave badly," says Ethier.

He compared cells to computers with a lot of different software programs on them.

"As long as those software programs are working fine, your computer is humming along nicely and doing nice things for you. But sometimes those programs get corrupted. They get viruses. Now the programs and the computer are not behaving well.

"Genes that regulate how a cell behaves are like software programs. When they get mutations, they get actual chemical changes in the DNA that don't ever go away. When those mutations occur, they are fixed and forever. The instructions, which come from those genes, are now incorrect instructions and don't respond to instructions like they should."

Dumb vs. smart cancer

Despite early victories in using genomics to battle cancer, unraveling these cancer mysteries will continue to be challenging.

Early successes, such as with Fitch's leukemia, are due largely to finding less complicated genetic mutations, or oncogenes.

"Why does it work so well in CML (chronic myelogenous leukemia)? It's a simple reason. CML is what we call a dumb cancer. It's got one oncogene and it's the only driving oncogene in the cancer, so if you knock it out, you get a good effect," says Ethier.

"Unfortunately, most cancers are smarter than that. Most cancers have multiple oncogenes and they talk to each other," says Ethier.

One case in point is the melanoma oncogene, RAF, that is resistant to conventional chemo and radiation. A new drug, Vemurafenib, targeted it and temporarily worked.

"The melanomas disappear, but a year later, they are back," says Ethier. "We're making progress, but we're not there yet."

Genomic sequencing technology, he adds, will help researchers get beyond identifying single oncogenes, but to know all of the oncogenes. Cancer patients will eventually have "oncogene signatures" that are unique to them.

Preventing cancer

Last month, a nationally respected cancer expert, Dr. Olufunmilayo "Funmi" Olopade, gave a talk filled with hope and inspiration to students and faculty at MUSC on how genetics and genomics are revolutionizing cancer care.

Olopade, who was appointed by President Barack Obama to serve on the National Cancer Advisory Board, not only discussed how genomics will drive treatment but how genetics will help preempt disease development.

Olopade is an expert on individualized treatment for breast cancer and related a story about a patient with the BRCA1 gene. After she was treated for breast cancer at ages 24 and 35, Olopade strongly urged her to have her ovaries removed. She didn't and died from ovarian cancer at age 43.

"If you have BRCA1 breast cancer, you better do something with your ovaries," she says.

"We're now defining what people need - genetic testing and counseling - in how we preempt the disease," says Olopade, adding that genetic tests should soon be considered as common in disease prevention as cholesterol tests are for heart disease.

As for genomics, she says the progress has been exciting. Mapping a person's genome used to take a year. Now it takes about a day.

"It's exciting times to begin to understand the human genome," says Olopade. "It will transform the way we think about risk groups, from race to their genome."

Reach David Quick at 937-5516.