Akademik Veri Yönetim Sistemi
II. International Hereditary Cancers Congress, Antalya, Türkiye, 5 - 08 Şubat 2026, sa.212, ss.157-160, (Tam Metin Bildiri)
[Abstract:0212]
From Prenatal Screening to Maternal Diagnosis: A Case Report of Lynch Syndrome Incidentally Detected via NIPT
Gökçehan Erdiman1, Şeyma Doğan1, Zafer Bütün2, Ebru Erzurumluoğlu Gökalp1, Sinem Kocagil1
1Eskişehir Osmangazi Üniversitesi Tıp Fakültesi Tıbbi Genetik A.B.D.
2BTN Klinik/Eskişehir/Türkiye
Objective: The noninvasive prenatal test (NIPT) is a screening test for fetal chromosomal aberrations during
pregnancy. While the maternal plasma cfDNA pool is predominantly derived from maternal hematopoietic cells,
approximately 5–15% originates from placental syncytiotrophoblasts. However, in the presence of maternal
malignancy, tumor-derived DNA fragments released via neoplastic cell lysis contribute to this pool, enabling the
incidental detection of occult maternal cancers. Atypical genomic profiles characterized by multiple
chromosomal aneuploidies or widespread segmental unbalanced rearrangements absent in the fetus are
observed in 0.03–0.12% of NIPT series. These findings serve as robust biomarkers for maternal neoplasia,
carrying a malignancy risk of approximately 6.4%-73.0%. In this report, we present the diagnostic management
of a patient found to have a complex chromosomal anomaly during routine fetal NIPT screening, which
ultimately led to the diagnosis of MLH1-associated Lynch syndrome in a large family.
Case: A 29-year-old pregnant woman with no known chronic illness or active symptoms presented at 12 weeks’
gestation for routine prenatal screening. NIPT showed a complex genomic profile, including a high-risk result for
trisomy 8 and trisomy 13, an approximately 70-Mb duplication involving 7q21.13–q36.3, and a sex chromosome
abnormality (XY/X). In light of NIPT findings, patient was referred to perinatology, oncology, and hematology
clinics. Further diagnostic imaging was undertaken and revealed a poorly differentiated mucinous
adenocarcinoma at the hepatic flexure extending into the proximal transverse colon, radiologically consistent
with T3–T4 stage and regional lymphadenopathy. The patient underwent a right hemicolectomy at 20 weeks’
gestation, with an uncomplicated perioperative and obstetric course. Concurrently, karyotype analysis and
microarray analysis from amniocentesis material done for fetal chromosomal abnormalities revealed normal
results as well as maternal peripheral blood karyotyping. In detailed pedigree analysis, it was noted that
colorectal carcinoma and endometrial carcinoma was diagnosed in maternal relatives of the proband. A
hereditary cancer panel identified a pathogenic variant NM_000249.4:c.790+1G>A in MLH1 gene. Following
diagnosis, cascade testing was initiated in the extended family. Segregation analysis in eight relatives with a
history of colorectal cancer confirmed that four individuals carried the same heterozygous variant. Accordingly,
genetic counseling was provided and tailored surveillance protocols were implemented for all at-risk family
members.
Conclusion: NIPT functions as a 'liquid biopsy' that extends beyond fetal screening to facilitate the
presymptomatic detection of maternal malignancies. Currently, no guidelines exist to classify a NIPT result as
suspicious of an occult malignancy. According to the Maastricht criteria, the presence of more than two
chromosomal aberrations, segmental aneuploidies affecting oncogenes or tumor suppressor genes, trisomy 12,
trisomy 8, trisomy 9, or monosomies indicates a high-risk category, warranting immediate oncologic evaluation.
In such clinical scenarios, a thorough family history is critical for guiding the diagnostic algorithm and elucidating
the underlying genetic etiology. As evidenced by this case of Lynch syndrome, a multidisciplinary approach
significantly enhances early diagnosis, improves maternal prognostic outcomes, and facilitates the identification
of at-risk relatives.
Keywords: Non-invasive prenatal testing (NIPT), Lynch syndrome, Maternal malignancy, MLH1 gene, Colorectal
cancer
From Prenatal Screening to Maternal Diagnosis: A Case Report of Lynch Syndrome Incidentally Detected via NIPT
Gökçehan Erdiman1, Şeyma Doğan1, Zafer Bütün2, Ebru Erzurumluoğlu Gökalp1, Sinem Kocagil1 1Eskişehir
Osmangazi University, Faculty of Medicine, Department of Medical Genetics, Eskişehir,Türkiye 2BTN
Klinik/Eskişehir/Türkiye Introduction and Aim Non-invasive prenatal testing (NIPT) has become an integral
component of contemporary prenatal screening for fetal chromosomal abnormalities through the analysis of
cell-free DNA (cfDNA) in maternal plasma. In pregnancies at increased risk for common autosomal aneuploidies,
NIPT is recommended as a screening test, and positive results should be confirmed by invasive diagnostic
procedures. Although the circulating cfDNA pool is derived predominantly from maternal hematopoietic cells,
approximately 5–15% originates from placental syncytiotrophoblasts (the fetal fraction). While NIPT is primarily
designed to interrogate fetoplacental genetic material, its genome-wide scope can also detect signals originating
outside the fetoplacental unit. In pregnant individuals with malignancy, circulating tumor DNA (ctDNA) released
through tumor cell apoptosis and/or necrosis may contribute to the maternal cfDNA pool and alter the observed
genomic profile. Accordingly, beyond its intended screening indication, NIPT may function as an incidental
“liquid biopsy” for otherwise asymptomatic maternal neoplasms. Incidental detection of maternal malignancy
through NIPT is uncommon but has been extensively discussed in the literature. Large population-based studies
estimate the prevalence of atypical NIPT findings suggestive of malignancy at approximately 0.01–0.03% [1–3].
Although this frequency is low, the risk of maternal malignancy increases substantially when complex genomic
patterns such as multiple chromosomal aneuploidies and/or genome-wide segmental copy-number variants
(CNVs) are identified. Depending on the platform and the interpretation framework, the reported positive
predictive value (PPV) for malignancy in this setting ranges from 6.4% to 73%. In particular, unexplained multiple
chromosomal aberrations, rather than an isolated classic aneuploidy, are considered a strong predictor of
maternal neoplasia, and several national series have reported PPVs approaching 70% in this subgroup [2,4].
Despite the growing number of published cases, there are currently no standardized international guidelines for
the clinical management of pregnant individuals with incidental NIPT findings raising suspicion for maternal
malignancy. Nonetheless, current expert opinions and the Maastricht criteria propose that specific patterns such
as trisomies associated with hematologic malignancies (e.g., trisomy 8, 9, and 12), complex profiles with more
than two aneuploidies, monosomies, or segmental imbalances involving oncogene/tumor-suppressor loci should
be regarded as high-risk and prompt urgent multidisciplinary oncologic evaluation [Table 1] [2,4,6]. Here, we
report a case that illustrates the diagnostic cascade initiated by incidental NIPT findings. Following the detection
of a complex genomic profile on routine NIPT for fetal aneuploidy screening, and further evaluation informed by
a positive family history, the patient was diagnosed with colorectal adenocarcinoma and Lynch syndrome.
Subsequent family screening identified four additional individuals carrying the same pathogenic variant. Lynch
syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants in
DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM, and it confers an increased risk of
several malignancies—most notably colorectal and endometrial cancer, as well as cancers of the ovary, stomach,
small intestine, urinary tract, hepatobiliary system, brain, and skin [7,8]. Through this case, we discuss the
management of incidental NIPT findings suggestive of maternal malignancy during pregnancy and emphasize the
role of genetic counseling. Case Report A 29-year-old primipara with no known chronic medical conditions and
no active symptoms presented to our center at 12 weeks of gestation for routine NIPT for fetal aneuploidy
screening. During pre-test genetic counseling, the family history was notable for suspected colon cancer in her
mother and one brother; therefore, relatives invited and offered to take next generation sequencing (NGS)-
based hereditary cancer panel testing in parallel with the prenatal screening process of the proband. NIPT
indicated high-risk results for trisomy 8 and trisomy 13 and revealed a complex genomic profile, including an
approximately 70-Mb duplication spanning 7q21.13–q36.3 and a sex-chromosome abnormality (XY/X, as
reported) [Table 2]. When the NIPT findings were scored according to the Maastricht criteria, the total score was
9: 3 points for more than two chromosomal abnormalities; 2 points for an approximately 70-Mb 7q21.13–q36.3
duplication containing multiple cancer-relevant genes; 2 points for monosomy X; 1 point for trisomy 8; and 1
point for the co-occurrence of trisomy 8 and trisomy 13. Because the score was ≥3, the case was classified as
high risk for maternal malignancy according to the Maastricht criteria. In line with these findings, the patient
received genetic counseling and was referred to Perinatology clinic for invasive prenatal diagnostic testing as
well as Medical Oncology and Hematology for evaluation of possible maternal malignancy. In parallel, the
hereditary cancer panel workflow was expedited. At 16 weeks of gestation, amniotic fluid was obtained by
amniocentesis for prenatal diagnosis, and karyotyping, chromosomal microarray analysis, and QF-PCR were
performed. Maternal peripheral blood was also collected for karyotype analysis. All results were normal. Breast
ultrasonography, axillary ultrasonography, and neck ultrasonography were unremarkable. Abdominal
ultrasonography, however, demonstrated a “pseudokidney” appearance with hypoechoic wall thickening and
luminal narrowing (25–30 mm) extending approximately 11–12 cm at the level of the hepatic flexure. Based on
these findings, colonoscopy was performed. It revealed a circumferential ulcerated exophytic mass with necrotic
exudate, extending approximately 10–12 cm from the mid-ascending colon to the hepatic flexure and proximal
transverse colon; multiple biopsies were obtained. Histopathological evaluation revealed a poorly differentiated
adenocarcinoma with a mucinous component, consistent with colon adenocarcinoma. Staging CT performed at
19 weeks of gestation showed findings consistent with at least cT3 (possibly cT4) right-sided colonic tumor
invasion and mesenteric lymph node enlargement, without evidence of distant organ metastasis. A right
hemicolectomy was performed at 20 weeks of gestation, with no perioperative or obstetric complications.
Hereditary cancer panel testing identified a heterozygous MLH1 splice-site variant, NM_000249.4:c.790+1G>A,
previously reported as pathogenic in ClinVar and classified as pathogenic according to ACMG/AMP criteria (PS4,
PS3, PVS1, PM2). The patient was therefore diagnosed with Lynch syndrome [Figure 1]. Following the molecular
diagnosis, segregation analysis was performed in eight family members (including individuals with a history of
colorectal cancer), and the same heterozygous variant was detected in four relatives. Genetic counseling was
provided to all at-risk individuals, and personalized surveillance programs were planned. Other at-risk relatives
who could not undergo segregation analysis were also invited to our center for testing upon request [Figure 2]
Discussion and Conclusion This case highlights that NIPT may function as an incidental “liquid biopsy” beyond
fetal aneuploidy screening, enabling presymptomatic detection of maternal malignancy. At present, no
universally accepted guideline exists for classifying NIPT results with respect to the risk of occult maternal
malignancy. Nevertheless, this case underscores the clinical utility of the Maastricht criteria as a practical
framework informing contemporary diagnostic algorithms. In particular, prompt management of individuals
classified as high risk (Maastricht score ≥3) is essential. Such cases should receive timely genetic counseling
during pregnancy and undergo multidisciplinary assessment involving Perinatology, Medical Oncology, and
Hematology. Although NIPT was performed solely as a screening test in our patient, this case reinforces the
importance of obtaining a comprehensive family history during pre-test counseling. Systematic assessment of
familial cancer history even at the prenatal screening stage is critical for appropriate management of the
diagnostic pathway and for elucidating the underlying genetic etiology. More broadly, careful interpretation of
genetic tests in light of the current literature and a multidisciplinary approach can facilitate early diagnosis and
improved maternal prognosis, and it may also enable the identification of additional affected relatives beyond
the original testing indication, as observed in this family Table 1. Maastricht Criteria [4] Criteria Score Number of
aberrations (abnormalities) > 2 3 Monosomy 2 Segmental aneuploidies with presence of an oncogene or tumor
suppressor gene 2 Trisomy 12 2 Trisomy 9 2 Trisomy 8 1 Two trisomies in total 1 High significance score of the
aberration 1 Probability level Total score No suspicion < 2 Mild suspicion 2 Strong suspicion ≥ 3 Table 2. Z-scores
and ratios of chromosomal abnormalities detected in our patient Finding Risk classification Result Trisomy 13
High risk Z-score: 29.643 (reference: −3 < Z-score < 3) Trisomy 7 High risk Z-score: 7.462 (reference: −3 < Z-score
< 3) Finding Risk classification Result Trisomy 8 High risk Z-score: 17.775 (reference: −3 < Z-score < 3) Trisomy
7q32→qter High risk Complex sex chromosome anomaly High risk Ratio: 9.89% (low-risk threshold: < Z score <
3) Figure 1. Integrative Genomics Viewer (IGV) screenshot of the MLH1 splice-site variant
(NM_000249.4)c.790+1G>A detected by NGS using a hereditary cancer panel. Fgure 2. Famly members (mother
and brother) n whom the heterozygous MLH1 (NM_000249.4):c.790+1G>A varant was dentfed by Sanger
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