Fall 2015

The Loaded Dice

In rare cases, prenatal screening finds genetic abnormalities that point to malignancies, says Tufts scientist

By Jacqueline Mitchell

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DNA fragments of the kind that figure in Bianchi’s work appear in red in this transmission electron micrograph. Illustration: Biology Pics/Science Source

When Marin Mejia got pregnant at age 39, she had a blood test to screen her fetus for genetic abnormalities. Children born to mothers 35 and older are at greater risk for Down syndrome and other conditions. The baby was fine. Mejia, however, was not. The genetic screening detected abnormalities that were subsequently shown to be caused by a tumor releasing abnormal DNA fragments into her blood.

Sophisticated and highly sensitive noninvasive prenatal testing, like the kind Mejia received, was first introduced in 2011. “It picks up very unexpected things”—including imbalances in the genome of the expectant mothers that may be associated with a tumor, says Diana W. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics and Gynecology at Tufts School of Medicine.

For a paper published in the Journal of the American Medical Association (JAMA) in June, Bianchi and her research team analyzed the noninvasive prenatal tests of 125,426 women whose fetuses were screened for chromosomal defects; they had abnormal test results but delivered healthy babies. Ten of these women’s doctors told the laboratory that the women had been diagnosed with cancer after the prenatal tests were performed.

Unlike amniocentesis—an invasive prenatal test that samples the fluids directly around a developing fetus for genetic material—noninvasive tests analyze the genome of a fetus by sequencing DNA fragments floating in the mother’s blood. As a fetus develops, some placenta cells die and release fragments of the baby’s DNA into the mother’s bloodstream. By the tenth week of pregnancy, says Bianchi, fetal DNA makes up as much as 10 percent of the DNA fragments in a mother’s bloodstream, and the amount continues to increase as the pregnancy progresses.

The noninvasive screening, which can sample 20 million to 25 million fragments of DNA, does turn up the occasional false result. “We know of cases where the blood test is saying the baby is going to be a boy, and then the ultrasound shows it’s a girl,” Bianchi says. “And then we might find out the mother forgot to mention that she had a kidney transplant from her brother, so what’s really being detected is genetic material from the kidney,” she says. “But we didn’t know that tumors could be a source [of the false-positive DNA results] until 2013.”

That was when a case report crossed Bianchi’s desk for a professional journal she edits, Prenatal Diagnosis, about a mother whose test showed a false-positive result for two chromosomal abnormalities. Shortly after giving birth to a healthy son, the woman was diagnosed with cervical cancer. DNA from the cancer, the initial study authors reasoned, must have triggered the false- positive reading.

Bianchi, who is also executive director of the Mother Infant Research Institute at Tufts Medical Center, and her colleagues at Illumina—one biotech company that manufactures the genetic screening test—started keeping track of such cases, asking doctors to voluntarily report when women with abnormal noninvasive prenatal tests who delivered healthy babies later turned up with cancer.

“We had no sense of how common it was or what you should do about it,” she says.

Tracking the Tests

Until recently, the consent forms for the prenatal tests didn’t mention the possibility of producing findings about the health of the mother, says Bianchi. In a recent commentary in the journal Nature, she recommended that the consent forms be revised to indicate that expectant mothers and the health professionals who care for them need to be aware of such potential outcomes. “It’s a problem, because some women, as soon as they get a positive screening test, are terminating their pregnancies without realizing the abnormal result could be from their own DNA and not the baby’s,” she says.

“We only detected the multiple chromosome abnormal results in 39 women out of 125,426, so it’s an extremely rare finding.” —Diana Bianchi

For two years, Bianchi and her colleagues tracked prenatal tests that yielded unusual results. The lengthy tracking meant that “later patients in the study got the benefits of earlier patients,” Bianchi says. “The word was out on the street about certain unusual DNA findings being associated with maternal cancer. The biggest red flag was the presence of more than one chromosomal abnormality detected,” she adds, because if a fetus really has more than one, it probably wouldn’t survive very long. Instead, multiple abnormalities more likely signal the presence of tumor DNA.

When Marin Mejia’s test results came back with four chromosomal abnormalities, her doctors were more worried about her than her baby. She got a cancer screening right away and learned she had anal cancer while she was still pregnant with her son, Owen, who was born healthy. She chose to deliver early so she could begin her cancer treatment.

“We felt it was so important to publish our results in a broad-impact journal like JAMA,” says Bianchi. “We wanted obstetricians, family practitioners and oncologists to be aware that a pregnant woman could have these abnormal results, and it could be cancer. In three of the women in our study, their cancers were definitely detected because of the abnormal prenatal test results.”

Bianchi stresses that the prenatal test will never be used as a cancer screen. “We only detected the multiple chromosome abnormal results in 39 women out of 125,426, so it’s an extremely rare finding,” she says. “Of those, we know of only 10 who have had cancer.”

The noninvasive prenatal test is marketed by several companies, including Illumina, which funded Bianchi’s study and for which she serves as an expert clinical advisor. Over the past four years, more than 2 million women have undergone the screening worldwide. Such tests are generally reserved for high-risk pregnancies for certain genetic or chromosomal defects, including Down syndrome. In the United States, insurance covers the tests for women who are 35 or older, who have a family member with Down syndrome or whose fetuses have had structural abnormalities found by ultrasound examination.

To follow up on their retrospective study—in which the researchers looked at the test results of women who later were diagnosed with cancer—Bianchi wants to conduct a prospective study to look for patterns that might suggest which mothers are at risk for cancer. Such a finding could help physicians and others to improve care for these women.

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.

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