Natural history and evaluation of abnormal or nonreportable NIPT results and its association with maternal neoplasia

National Human Genome Research Institute

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Abstract

Since it became clinically available, noninvasive screening for fetal aneuploidy by sequencing cell-free (cf) DNA fragments that circulate in maternal blood has disrupted established global paradigms for prenatal care. In general, these tests work by mapping sequenced DNA fragments and determining if there are excess or reduced copy numbers compared to a reference genome. Commercial laboratories in the United States each have their own proprietary analytic algorithms. Around 1% of the time, a non-reportable test result is generated that is due to either technical issues (such as insufficient DNA or low fetal fraction in the sample) or biological issues (such as a twin demise or confined placental or maternal mosaicism). In 2019 we launched the Incidental DEtection of maternal Neoplasia Through non-Invasive cell-free DNA analysis study, known by its acronym as the IDENTIFY study. Participants undergo an initial evaluation at the Clinical Center to diagnose possible neoplasia. All collected clinical, laboratory and imaging information is discussed in monthly multidisciplinary team meetings. If neoplasia is discovered, results are shared with participants and referring physicians and guide subsequent clinical management. Participants will be followed for up to five years post-partum to collect all available medical information. To date we have enrolled over 250 participants. They have come from all over the US, six have come from Canada, and one has come from Israel. Approximately 70% of the cohort is white, non-Hispanic and 30% of the cohort is Black, Asian, Hispanic, or multiple races. An occult malignancy has been detected in around half of our participants. Lymphoma is the most common cancer diagnosis, followed by colorectal cancer and breast cancer. Extremely rare tumors, such as adrenocortical carcinoma, have also been detected. Other biological explanations for participants’ cfDNA results have included benign uterine leiomyomas, confined placental mosaicism, and clonal hematopoiesis of indeterminate potential. In December 2024, we published findings from an initial cohort of 107 participants with complete clinical data. Of these 107 participants, 48.6% had an occult malignancy. Whole-body MRI was the most effective method for detecting malignancies. Physical examination and laboratory tests were normal in most participants, and therefore, were not useful in distinguishing which participants had cancer. Blinded review of the cfDNA sequencing traces has allowed us to identify distinct sequencing patterns between malignant and non-malignant findings. cfDNA results showing a combination of both chromosomal gains and losses appear to have the highest risk of malignancy. Cancer was present in 95.6% of participants with this sequencing pattern. Pregnant individuals with this sequencing pattern require prompt cancer screening that includes whole-body imaging. To continue to raise awareness among oncologists, obstetric care, and genetics providers, Dr. Bianchi and Amy Turriff, CGC, have given numerous national and international plenary presentations at annual professional society meetings, Continuing Medical Education conferences and Grand Rounds hospital presentations.