Faster, cheaper gene sequencing points to greater cancer understanding, GHSU researchers say

Sequencing becomes easy, inexpensive



A common mutation in a tumor-suppressing gene could explain why blacks are more likely to get early breast and colon cancer, researchers at Georgia Health Sciences University said.

The ability to more quickly and cheaply do gene sequencing, or decoding, means it could be opened up soon to more than just cancer patients, researchers said.

With new equipment that allows them to sequence an entire genome (the human genetic code) overnight for about $6,000, the researchers at the university’s cancer center said they are zeroing in on unique mutations that could point the way to targeted treatments in some difficult-to-cure cancers.

The new gene sequencing allows them to paint both a global picture of cancer susceptibility among different populations and also a highly individualized portrait of a patient and that particular cancer to aid treatment.

Researchers were trying to find the genetic answer for why black patients appear to get breast and colon cancers at younger ages than whites and Asians. Looking at the genomes of modern African, African-American, European and Asian populations, the researchers focused on a single amino acid difference in the p53 tumor suppressor gene, which is more prevalent in Africans and African-Americans than in others.

Those with that particular gene profile got particular kinds of breast and colorectal cancer early, but not others, which would show it is not caused by social factors such as lack of access to medical care, said Dr. Phillip Buckhaults, an associate professor at the cancer center.

Gene expression analysis of human cell lines of the two variants of the p53 gene found that the African line failed to activate a key protein that is also involved in persuading undifferentiated stem cells to turn into other kinds of cells.

“Every time you are exposed to something that might induce DNA damage and cause a mutation in a stem cell that could turn it into cancer, the new p53 variant responds by activating this gene called PRDM1 and causes that cell to terminally differentiate,” Buckhaults said. “So we are protected from cancer through our mortality.”

The key now would be to screen for the other variant of p53, Buckhaults said.

“What we would like to do is genetically test people and see if they are at high risk or low risk for cancer, and, if they are at high risk of getting cancer early, modify when they should get screened for cancer,” he said.

Much of what GHSU is discovering comes from sequencing a person’s normal genome and sequencing the cancer, in essence running a blood sample against a tissue sample from the tumor and noting the mutations, said Dr. Lesleyann Hawthorn, the director of shared resources at the cancer center.

“You can target the tumor because that’s the only place you’re seeing the mutations,” she said.

GHSU is doing that clinically with breast cancer but would really like to focus on “triple negative” breast cancer, which lacks the hormone receptors and HER2 receptors that would lead to targeted treatments, Hawthorn said.

Survival rates for estrogen-positive cancer are over 90 percent, versus about 14 percent for triple negative, she said.

“It is really, really bad,” Hawthorn said. “And it happens in African-Americans at a really young age, before they’re 45. It is something that we need to be focusing on.”

The center has sequenced 15 triple negative tumors and is focusing on a couple of mutations, she said.

“One of them happens to be p53, unfortunately,” Hawthorn said. The p53 mutation, or trying to restore its function in cells where it has been lost, has been the focus of decades of efforts without much clinical success.

“It’s almost in every single (cellular) pathway,” Hawthorn said. “It’s a difficult one, so you have to find something upstream or downstream in that pathway to target it.”

There could be an additional benefit for cancer patients who are getting sequenced, Buckhaults said.

“While sequencing people for cancer, we discovered mutations that didn’t have anything to do with cancer but that we would like to tell these people about,” he said, including a mutation that could put them at higher risk of a sudden heart attack. “They are walking around with these mutations and don’t know it. We discovered this by chance.

“So what we want to do is begin sequencing people who come to GHSU for treatment, initially for cancer but eventually for everything. We will sequence their genome if they show up with a broken arm, much the way we would take their temperature.”

Some places are already doing this, Hawthorn said.

“A lot of people are just sequencing newborns now completely,” she said. “And actually insurance companies are paying for it because it means that they can identify things that can be treated proactively before any kind of disease develops. So I think it will probably get to that stage.”

Where it once took a decade and a billion dollars to complete a whole genome, it could very soon take hours and cost about $1,000. Although there are fears that that could lead to genetic discrimination, Hawthorn said all of that sequencing will just lead to more questions.

“I think we are just going to find out it is a lot more complicated than we thought, as usual,” she said. “The more we find out, the more we realize we don’t know.”



Tue, 01/23/2018 - 23:44

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