Gene panel screens dozens of genes for cancer-associated mutations


April 16, 2014
Health, Technology

As many as 10 percent of women with a personal or family history of breast or ovarian cancer have at least one genetic mutation that, if known, would prompt their doctors to recommend changes in their care, according to a new study by researchers at the Stanford University School of Medicine.

The women in the study did not have mutations in BRCA1 or BRCA2 (mutations in these genes are strongly associated with hereditary breast and ovarian cancer), but they did have mutations in other cancer-associated genes.

The study was conducted using what’s known as a multiple-gene panel to quickly and cheaply sequence just a few possible genetic culprits selected by researchers based on what is known about a disease. Although such panels are becoming widely clinically available, it’s not been clear whether their use can help patients or affect medical recommendations.

A middle ground

“Although whole-genome sequencing can clearly be useful under the right conditions, it may be premature to consider doing on everyone,” said James Ford, MD, who directs Stanford’s Clinical Cancer Genetics Program. “Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information.”

Ford, an associate professor of medicine and of genetics, is the senior author of the study, published April 14 in the Journal of Clinical Oncology. Allison Kurian, MD, assistant professor of medicine and of health research and policy, and associate director of the Clinical Cancer Genetics Program, is the study’s lead author.

Ford was a co-author of a recent paper in The Journal of the American Medical Association that highlighted the challenges and opportunities of making whole-genome sequencing clinically available for seemingly healthy people. Although that study showed that whole-genome sequencing can be potentially life-saving, the challenges involved in sequencing the billions of nucleotides that make up all of a person’s DNA, and then translating the results into clinical care recommendations, is significant.

“This study indicates that using gene panels to screen for potentially harmful variants can be clinically useful in certain groups of patients,” said  Kurian. “It also shows that patients, some of whom had given blood samples for research as many as 10 years earlier, are willing and interested to receive this type of follow-up information and to incorporate it into their health care plans.”

Quicker, easier and cheaper

Gene panels allow researchers to learn the sequences of several genes simultaneously from a single blood sample. It stands to reason that screening for mutations in just a few select genes is quicker, easier and cheaper than whole-genome sequencing. The technique usually focuses on fewer than 100 of the approximately 21,000 human genes. But until now, few studies have investigated whether homing in on a pre-determined panel of suspects can actually help people.

In the study, Kurian and Ford assessed the sequences of 42 genes known to be associated with the development of breast or other cancers, or involved in DNA repair pathways that nip potentially dangerous mutations in the bud. Blood samples in the study came from 198 women who underwent BRCA1 and BRCA2 testing at the Stanford Clinical Cancer Genetics Program between 2002 and 2012. At the time of the testing, the women were asked if they would like to donate an additional blood sample for future research.

Of the 198 women, 57 carried BRCA1/2 mutations. Ford and Kurian found that 14 of the 141 women without a BRCA1/2 mutation had clinically actionable mutations in one of the 42 genes assessed by the panel. (An actionable mutation is a genetic variation correlated strongly enough to an increase in risk that clinicians would recommend a change in routine care — such as increased screening — for carriers.)

Eleven of the 14 women were reachable by telephone, and 10 accepted a follow-up appointment with a genetic counselor and an oncologist to discuss the new findings. The family members of one woman, who had died since giving her blood sample, also accepted counseling. Six participants were advised to schedule annual breast MRIs, and six were advised to have regular screens for gastrointestinal cancers; many patients received more than one new recommendation.

One woman, with a history of both breast and endometrial cancer, learned she had a mutation that causes Lynch syndrome, a condition that increases the risk of many types of cancers. As a result, she had her ovaries removed and underwent a colonoscopy, which identified an early precancerous polyp for removal.

Guidance for care decisions

“An important question about the use of these gene panels is whether they can allow us to provide additional genetic guidance and screening,” Kurian said. “We found that the participants were interested and willing to receive the additional information, and they were generally pleased at the results, which helped them make decisions about their clinical care.”

Screening with gene panels does not, however, eliminate the problem of variants of uncertain significance. This term is used when a gene sequence deviates from the consensus, but the clinical effect of that change is unknown. Each of the 141 women in the study had about two variants of uncertain significance in the 42 genes studied.

“This problem is shared with whole-genome sequencing,” Ford said, “and should subside as we gather ever more data on the effect of specific mutations in these genes.” The National Institutes of Health-sponsored Clinical Genome Resource, or ClinGen, was created to speed the identification and aid in the interpretation of clinically important variants.

Yet even though the study shows that gene panels can be useful in some groups, it may be some time before they could be routinely used in the general population, the researchers said.

“It’s a slippery slope at the moment,” Ford said. “We need to know how prevalent these cancer-associated mutations are in the general population. We also need to be aware that, at least for a while, it’s very likely that every person will harbor one or more variants of uncertain significance. Is that information that a person would want to know? Is it helpful? In 10 years, this is likely to change as we learn more about the clinical significance of these changes.”

Other Stanford co-authors are genetic counseling program manager Meredith Mills; genetic counselor Kerry Kingham; research associate Lisa McPherson, PhD; professor of health research and policy Alice Whittemore, PhD; senior research scientist Valerie McGuire, PhD; and associate professor of medicine Uri Ladabaum, MD. Researchers from the San Francisco-based Invitae Corp., a genetic-testing company, were also co-authors. Invitae sequenced the genes in the study and helped to fund the study.

Additional funding came from the Breast Cancer Research Foundation, a Stanford Cancer Institute Developmental Research Award in Population Sciences, the Jan Weimer Junior Faculty Chair in Breast Oncology at Stanford and the National Institutes of Health (grant RR025744).


Gene panel screens dozens of genes for cancer associated mutations

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2 Responses to Gene panel screens dozens of genes for cancer-associated mutations

  1. Tanya Haar-14020892 April 23, 2014 at 12:08 pm #

    Cancer: A word that effects almost every person’s life. We have all lost loved one’s because of cancer. It is a disease not easily cured or detected. Some cures exist but lead to pain, nausea and much more side effects. Gene paneling can be the answer to a lot of questions concerning cancer. With this new technique scientist and doctors can search for altered genes leading to cancer, without harming the patient. It will make cancer diagnosis much easier and much more efficient.

    These tests can be done at any time and will indicate if a person is more prone to some cancers and with this information the person can change their lifestyle and check up intervals. This will lead to fewer deaths caused by cancer.

    I believe that this will be a major improvement in medicine and cancer treatment, as there are currently no tests available that can detect cancer at an early stage, which in more cases is vital. If a cancer has been detected too late, usually nothing can be done to save this persons life.

    I believe that every person that has had family members die of cancer should get tested.

  2. Michelle Adams (u14023432) April 22, 2014 at 12:28 pm #

    It is amazing how science and especially medicine has progressed. Not so long ago we knew nothing about genes and DNA, but now we know far more than we could have ever imagined. This knowledge enables us to solve certain problems that plague the human race. One of these problems is cancer. Cancer affects millions of people around the world each year. Although we have chemotherapy and radiation as ways to combat cancer, they are not as effective as they should be. Sometimes, even though people go through chemotherapy and radiation, their cancer is not cured forever. Sometimes the cancer is discovered too late and those treatments do not help the patient anymore.

    A variety of cancers need to be detected early in order for them to be cured. There are currently no tests or equipment that can detect cancer very early and nip it in the bud because medical technology is not that advanced yet, but could be in the future. Until then we need to find alternatives to detect cancer early, in order to cure it. Can this Multiple Gene Panel or the Whole-Genome Sequencing be the solution? Maybe.
    These tests can help people find out whether they are prone to certain cancers and can lead to them having check-ups more often and will help if cancer occurs to detect it early and could possibly safe that person’s life. There is a negative side to these tests as well. Do people really want to know if they are more prone to cancer and live their life always subconsciously afraid of getting cancer? Are the positives of knowing really more than the negative aspects?

    I think it should be up to each individual to decide whether they want to undergo these tests. I think these tests will make people who are prone to cancer take their health and check-ups seriously and will decrease the number of deaths due to cancer. It is better to know if you are prone to cancer than being oblivious and having it cost you your life.

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