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Brief Report |

Presymptomatic Identification of Cancers in Pregnant Women During Noninvasive Prenatal Testing

Frédéric Amant, MD, PhD1; Magali Verheecke, MD1; Iwona Wlodarska, PhD2; Luc Dehaspe, PhD2; Paul Brady, PhD2; Nathalie Brison, PhD2; Kris Van Den Bogaert, PhD2; Daan Dierickx, MD, PhD3; Vincent Vandecaveye, MD, PhD4; Thomas Tousseyn, MD, PhD5; Philippe Moerman, MD, PhD5; Adriaan Vanderstichele, MD2; Ignace Vergote, MD, PhD2; Patrick Neven, MD, PhD2; Patrick Berteloot, MD6; Katrien Putseys, MD7; Lode Danneels, MD8; Peter Vandenberghe, MD, PhD2,3; Eric Legius, MD, PhD2; Joris Robert Vermeesch, PhD2
[+] Author Affiliations
1Department of Obstetrics and Gynecology, Gynecological Oncology, Katholieke Universiteit (KU) Leuven–University of Leuven, University Hospitals, Leuven, Belgium
2Center for Human Genetics, KU Leuven–University of Leuven, University Hospitals Leuven, Belgium
3Department of Hematology, KU Leuven–University of Leuven, University Hospitals, Leuven, Belgium
4Department of Radiology, KU Leuven–University of Leuven, Leuven, Flanders, Belgium
5Department of Pathology, Translational Cell and Tissue Research, KU Leuven–University of Leuven, Leuven, Belgium
6Department of Obstetrics and Gynecology, Gynecologic Oncology, University Hospital, Leuven–General Hospital, Sint-Maarten Duffel, Belgium
7Department of Obstetrics and Gynecology, General Hospital H. Hart, Leuven, Belgium
8Department of Obstetrics and Gynecology, General Hospital Delta, Roeselare, Belgium
JAMA Oncol. 2015;1(6):814-819. doi:10.1001/jamaoncol.2015.1883.
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Importance  Noninvasive prenatal testing (NIPT) for fetal aneuploidy by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a major prenatal genetic test. Similar to placental DNA, tumor DNA can be detected in the plasma, and analysis of cell-free tumor DNA can be used to characterize and monitor cancers. We show that plasma DNA profiling allows for presymptomatic detection of tumors in pregnant women undergoing routine NIPT.

Observations  During NIPT in over 4000 prospective pregnancies by parallel sequencing of maternal plasma cell-free DNA, 3 aberrant genome representation (GR) profiles were observed that could not be attributed to the maternal or fetal genomic constitution. A maternal cancer was suspected, and those 3 patients were referred for whole-body diffusion-weighted magnetic resonance imaging, which uncovered an ovarian carcinoma, a follicular lymphoma, and a Hodgkin lymphoma, each confirmed by subsequent pathologic and genetic investigations. The copy number variations in the subsequent tumor biopsies were concordant with the NIPT plasma GR profiles.

Conclusions and Relevance  We show that maternal plasma cell-free DNA sequencing for noninvasive prenatal testing also may enable accurate presymptomatic detection of maternal tumors and treatment during pregnancy.

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Figure 1.
Whole-Body Diffusion-Weighted Magnetic Resonance Images

A, Ovarian carcinoma in patient 1. B, Follicular lymphoma in patient 2. C and D, Hodgkin lymphoma before (C) and after (D) treatment in patient 3. The arrowheads in all panels point to the tumor locations. D, Arrowheads point to areas of treatment response (complete remission).

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Figure 2.
Genome Representation (GR) Profile and Fluorescence In Situ Hybridization (FISH) Images of Ovarian Carcinoma (Patient 1)

A-D, All panels present both chromosome GR profiles (chromosomes 6, 7, 9, and 18; left panel halves) and validation by FISH analyses of large tumor cells in biopsy specimens (right panel halves). In the GR profiles, the positions of the examined genes on the cytoband are indicated by the arrows; the vertical graphs represent the actual GR profiles: dotted lines on either side of the axis, plus or minus 1.5x; red areas, likely deleted regions; and blue areas, likely duplicated or amplified regions. All FISH analyses were performed on 5-µm sections from snap-frozen biopsy tissue. The illustrated FISH probes include the following: A, IRF4 (6p24) double-color probe (red and green), probe used to proof copy number aberrations, and CEP6 probe (green) (the CEP6 signals are hidden in the amplified IRF4 area, hence no indicating arrowheads); B, TCRB (7q35) double-color probe (red and green), probe used to proof copy number aberrations, and CEP7 probe (green) (arrowheads); C, JAK2 (9p24) double-color probe (red and green), probe used to proof copy number aberrations, and CEP9 (green) (arrowheads); and D, BCL2 (18q21) double-color probe (red and green), probe used to proof copy number aberrations, and CEP18 probe (blue). The inverted coloring in panel D is required to visualize the blue probes (spectrum aqua) against the background. A-C, Note numerous and amplified signals of IRF4, TCRB, and JAK2, evidencing gain of these regions in tumor cells detected by GR profiling. D, Two BCL2 and 5 CEP18 signals confirm loss of the 18q material in carcinoma cells.

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Figure 3.
Array Comparative Genomic Hybridization (CGH) Analysis, Chromosomal Abnormalities, and Genome Representation (GR) Profiles of Follicular Lymphoma (Patient 2)

A, In the array CGH analysis, the column labels represent the numbered chromosomes plus X and Y; the y-axis, represents the log2 of the intensity ratios; each graphed point, an array probe; and the boxed areas highlight the chromosomes detailed in panel B. B, Illustrated chromosomal abnormalities (arrowheads) related to the genomic imbalances in the GR profile of follicular lymphoma: [i(6)(p10) (gain of 6p/loss of 6q), dup(7)(q11q22), +dup(7)(q11q22) (gain of 7 and extra gain of 7q11q22), +11 (gain of 11), dup(12)(q13q15) (gain of 12q13q15), and dup(13)(q21q34) (gain of 13q21q34)]. C, The GR profiles of the 5 relevant chromosomes. The partial loss of 6q (but not the entire 6q) and lack of trisomy 7 and 11 in the GR profile of cell-free DNA is likely related to a subclonal/subregional appearance of these aberrations. For an explanation of the graphic conventions used in a GR profile, see the caption of Figure 2. As evidenced by chromosome 11 GR profile, no abnormalities were found.

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Figure 4.
Genome Representation (GR) Profile and Fluorescence In Situ Hybridization (FISH) Images of Hodgkin Lymphoma (Patient 3)

A-C, All panels present both chromosome GR profiles (chromosomes 8, 9, and 14; left panel halves) and validation by FISH analyses of Hodgkin and Reed-Sternberg cells from formalin-fixed paraffin-embedded biopsy tissue (right panels). In the GR profiles, arrows indicate the cytoband positions of the examined genes. For a further explanation of the graphic conventions used in a GR profile, see the caption of Figure 2. The illustrated FISH probes include the following: A, LSI MYC (8q24) double-color probe (red and green) and probe used to proof copy number aberrations; B, JAK2 (9p24) double-color probe, probe used to proof copy number aberrations, and CEP8 (blue, marked with arrowheads); and C, LSI IGH (14q32) double-color probe and probe used to proof copy number aberrations. The presence of 4 MYC signals (A), 2 CEP8 signals and amplification of JAK2 (B), and 6 IGH signals (C) confirms the gain of 8qter, 9pter, and chromosome 14 detected by GR profiling.

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