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Routine Prenatal Testing Detects Unknown Maternal Cancer

Series Demonstrates Incidental Detection of Unknown Maternal Malignancies during Routine Plasma-based Prenatal Testing

Maternal-fetal medicine specialists at Brigham and Women’s, Hospital were contributors to research conducted by other institutions, including Tufts Medical Center, on a case series showing incidental detection of occult maternal malignancies during prenatal testing using plasma cell-free DNA sequencing. Testing was performed as part of clinical prenatal aneuploidy screening, routinely used for the initial detection of Down syndrome.

“We noticed that in some cases where we were getting positive results in the prenatal aneuploidy screening, the mothers were later receiving a cancer diagnosis,” said Louise Wilkins-Haug, MD, PhD, Director of the Division of Maternal-Fetal Medicine. “After further research, we discovered that the extra DNA in these cases was found to originate from the mother, not the fetus or the placenta.”

The case series (JAMA. 2015;314(2):162-169.) included 125,426 samples from asymptomatic pregnant women undergoing clinical prenatal aneuploidy screening. The samples were submitted between February 15, 2012 and September 30, 2014. DNA sequencing identified positive results in 3,757 clinical samples (three percent of the total series) for chromosomes 13, 18, 21, X, or Y. Among the women with abnormal results, 10 were found to have cancer. In eight of these cases, detailed clinical and sequencing data were obtained (see Table). Maternal cancers most frequently were found in cases where more than one aneuploidy was detected.

Earlier Diagnosis, Non-specific in Cancer Type

The maternal malignancies that were ultimately diagnosed included a broad range of solid tumors and blood cancers. Earlier detection and commencement of treatment for the cancer resulted from the cell-free DNA testing. The testing, however, did not signal any particular type of cancer.

“There are a number of questions that remain,” said Dr. Wilkins-Haug. “We don’t know how often detection of these maternal malignancies will occur in the general population, or the incidence of other causes of abnormal results – including placental abnormalities or early loss of a twin. Down the road, we may find that additional testing should be performed as a routine part of the mother’s care in certain cases.”

Copy Number Changes in Eight Cases of Maternal Cancer

Figure 1: Whole-genome copy-number representation (normalized coverage)

Whole-exome view of copy-number gains and losses in plasma samples from women with known cancer. Smoothed normalized coverage (in black) is plotted along the genomic coordinates (x-axis), sorted by chromosome number and genomic location within the chromosomes. The data for all samples are shown as normalized on the same scale, on the left side of the y-axis (0.9-1.1). The scale chosen for this figure is less than 0.5-1.5 because of fractional representation of the tumor DNA in the mixed sample.

For some samples, the amplitude of the copy number variants exceeded the scale; the maximum deviation from expected diploid representation is shown as a percentage on the right side of the y-axis. Copy-number gains or losses relative to the diploid reference genome are shown as blue or red, respectively. If a trisomy was reported, the relevant chromosome is shown by a light blue bar. If a monosomy was reported, the relevant chromosome is shown by a light red bar. Cases 3 and 5 include replicates of the same blood sample, identified by an apostrophe (‘). Cases 1, 3, and 4 had longitudinal samples obtained. (JAMA. 2015;314(2):162-169.)


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