bims-ovdlit 2024-12-01 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2024–12–01
thirteen papers selected by
Lara Paracchini, Humanitas Research

High-grade serous carcinoma occurring after risk-reducing salpingo-oophorectomy in BRCA1/2 germline pathogenic variant carriers.
Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant.
Serous Tubal Intraepithelial Carcinoma (STIC): A Review of the Literature on the Incidence at the Time of Prophylactic Surgery.
The incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation.
Germline BRCA pathogenic variants and hematologic adverse events in patients with ovarian carcinoma receiving PARP inhibitors: a retrospective cohort study.
Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers.
Copy number alterations in normal breast tissues revealed by single-cell whole-genome sequencing.
Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications.
Minimal residual disease as a target for liquid biopsy in patients with solid tumours.
Azithromycin to Reduce Mortality.
Genomic landscape of cancer in racially and ethnically diverse populations.
Deciphering molecular relapse and intra-tumor heterogeneity in non-metastatic resectable head and neck squamous cell carcinoma using circulating tumor DNA.
Genome-wide methylation profiling of maternal cell-free DNA using methylated DNA sequencing (MeD-seq) indicates a placental and immune-cell signature.

J Natl Cancer Inst. 2024 Nov 23. pii: djae300. [Epub ahead of print]

High-grade serous carcinoma occurring after risk-reducing salpingo-oophorectomy in BRCA1/2 germline pathogenic variant carriers.

HEBON Investigators

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) effectively prevents high-grade serous carcinoma (HGSC) in BRCA1/2 germline pathogenic variant (GPV) carriers. Still, some women develop HGSC after RRSO without pathologic findings. This study assessed long-term incidence and risk factors for developing HGSC after RRSO without pathologic findings.
METHODS: BRCA1/2 GPV carriers were selected from Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) cohort. Follow-up data for HGSC after RRSO were obtained from the Dutch Nationwide Pathology Databank (PALGA) and confirmed by histopathological review. Cumulative incidence rates of HGSC were calculated using Kaplan-Meier analyses. Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with an increased risk of HGSC following RRSO without pathologic findings.
RESULTS: A total of 2519 women were included, with a median follow-up of 13.4 years (range: 0.0-27.6). The 20-years cumulative incidence rate of HGSC was 1.5% (95% CI: 0.0-2.1) for BRCA1 and 0.2% (95% CI: 0.0-1.4) for BRCA2 GPV carriers. All women who developed HGSC underwent RRSO after the recommended age. Incomplete embedding of the RRSO specimen (HR: 4.2, 95% CI: 1.4-12.6), higher age at RRSO (HR per year: 1.1, 95% CI: 1.0-1.1), and carrying a BRCA1 GPV (HR: 12.1, 95% CI: 1.6-91.2) were associated with increased risk of HGSC.
CONCLUSIONS: In BRCA1/2 GPV carriers, long-term incidence of HGSC after RRSO without pathologic findings was low. Strict adherence to guidelines regarding timely RRSO followed by complete specimen embedding can further reduce the risk of HGSC in the years following RRSO.

DOI: https://doi.org/10.1093/jnci/djae300
O G Open. 2024 Jun;pii: 009. [Epub ahead of print]1(2):

Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant.

Kristin M Tischer, Siddhartha Yadav, Debra Bell, Kathleen Hansen, Larissa N Veres, Brandon Maddy, Jamie N Bakkum-Gamez.

Background: Serous tubal intraepithelial carcinoma (STIC) lesions are the precursor to high grade serous ovarian carcinomas (HGSC) which have the highest mortality rate among gynecologic malignancies. Among women diagnosed with HGSC, 20% are found to be secondary to hereditary causes with the majority being associated with germline pathogenic variants (PVs) in BRCA1 and BRCA2 genes. Patients with a PV are high risk for developing HGSC, so it is recommended that they undergo risk reducing salpingo-oophorectomies in their 30s-40s. Opportunistic salpingectomy is the only ovarian cancer prevention method available for average risk patients. While STIC lesions are rare in average risk women, studies quote incidental STIC lesion findings in 1-7% of patients undergoing opportunistic salpingectomy.
Case: A 38-year-old woman (gravida 2, para 2) of Nepalese ethnicity had an incidental finding of a STIC lesion at the time of opportunistic salpingectomy for permanent sterilization at cesarean delivery. The STIC lesion was found using representative sampling of the fallopian tubes since the patient was considered average risk for ovarian cancer. This method is much less sensitive than SEE-FIM protocol which is used with known high-risk women. This ultimately led to discovery of a BRCA1 mutation in the patient.
Conclusion: SEE-FIM protocol is used to identify STIC lesions, but it is not routinely used on average risk patients' fallopian tubes. Using SEE-FIM protocol would lead to less missed STICs, but it is unclear how much extra cost and effort would be required to implement this. There are knowledge gaps when it comes to understudied populations and hereditary breast and ovarian cancer (HBOC) gene prevalence. Studies show that current BRCA prediction models underestimate HBOC gene prevalence in Asian populations. Diagnosing STICs in understudied populations could lead to the discovery of an HBOC PV which the patient may not have discovered until after a cancer diagnosis. Identification of a STIC in an average risk patient should lead to a referral for genetic counseling and screening.

DOI: https://doi.org/10.1097/og9.0000000000000009
Diagnostics (Basel). 2024 Nov 16. pii: 2577. [Epub ahead of print]14(22):

Serous Tubal Intraepithelial Carcinoma (STIC): A Review of the Literature on the Incidence at the Time of Prophylactic Surgery.

Daniela Luvero, Roberto Angioli, Erika Notaro, Francesco Plotti, Corrado Terranova, Anna Maria Angioli, Asia Festa, Andi Stermasi, Serena Manco, Miriana Diserio, Roberto Montera.

   BACKGROUND: Serous tubal intraepithelial carcinoma (STIC) is an early-stage cancerous lesion found in the fallopian tubes, often at the fimbrial end. It is strongly associated with high-grade serous carcinoma (HGSC), a highly aggressive type of ovarian cancer. STIC is considered a precursor to many HGSC cases, originating in the fallopian tubes. Its development is frequently linked to mutations in the TP53 gene, leading to the formation of a p53 signature, an early abnormality that may progress to HGSC. This signature is more common in BRCA mutation carriers, explaining the higher incidence of STIC in this group. The aim of this review is to evaluate the literature on the incidence of serous tubal intraepithelial carcinoma in patients (both BRCA-positive and BRCA-negative) undergoing preventive salpingo-oophorectomy, analysing the available data and identifying associations between specific characteristics and the onset of STIC.
METHODS: A comprehensive review of the literature from 2016 to 2023 was conducted using PubMed, focusing on studies analysing the incidence of STIC in BRCA-positive patients undergoing preventive salpingo-oophorectomy. Data on patient characteristics, interventions, outcomes, and incidence of STIC were extracted and analysed.
RESULTS: Nine international studies were included in the review, reporting varying incidences of STIC among patients undergoing salpingo-oophorectomy. The overall incidence of STIC in all the women included in the studies was 7.31%, while that in the BRCA-mutated women was approximately 6.08%. Notably, the presence of the TP53 signature was significantly associated with the occurrence of STIC.
CONCLUSIONS: The etiopathogenesis of STIC involves complex interactions between genetic, environmental, and molecular factors. Further research is needed to fully understand its mechanisms and identify additional risk factors beyond BRCA mutations. Establishing a national database of STIC cases could facilitate future research and improve patient outcomes.

Keywords:  BRCA mutations; HGSC; STIC; ovarian cancer; prophylactic surgery

DOI:  https://doi.org/10.3390/diagnostics14222577
Cancer. 2024 Nov 29.

The incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation.

Hereditary Breast Cancer Clinical Study Group

   BACKGROUND: The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated.
METHODS: A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow-up.
RESULTS: Thirty-four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan-Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%-4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%-5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first-degree relative with pancreatic cancer (hazard ratio, 4.75; 95% CI, 1.13-19.9; p = .03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5-year survival rate for the 34 cases was 8.8%.
CONCLUSIONS: The lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.

Keywords:  BRCA1; BRCA2; incidence; pancreatic cancer; survival

DOI:  https://doi.org/10.1002/cncr.35666
Oncologist. 2024 Nov 28. pii: oyae330. [Epub ahead of print]

Germline BRCA pathogenic variants and hematologic adverse events in patients with ovarian carcinoma receiving PARP inhibitors: a retrospective cohort study.

Carmine Valenza, Eleonora Nicolò, Marta Mongillo, Dario Trapani, Jalissa Katrini, Laura Boldrini, Luca Boscolo Bielo, Grazia Castellano, Lorenzo Guidi, Gloria Pellizzari, Jacopo Villa, Silvia Derio, Mariateresa Lapresa, Federica Gigli, Gabriella Parma, Emanuela Omodeo Salè, Enrico Derenzini, Giuseppe Curigliano, Nicoletta Colombo.

   BACKGROUND: Patients with a germline BRCA pathogenic variant (gBRCA-PV) and advanced high grade ovarian carcinoma (aHGOC) experience higher hematologic adverse events (HAEs) when receiving platinum salts and ionizing radiations, compared to non-carriers, due to a possible higher susceptibility of the hemopoietic stem cells to DNA targeting agents. However, the incidence of PARP inhibitor (PARPi)-related HAEs according to the gBRCA-PV status is currently unknown.
PATIENTS AND METHODS: We conducted a single-center retrospective cohort study to describe the occurrence of HAEs in patients with aHGOC receiving ≥8 weeks of maintenance PARPi in any line of therapy, comparing gBRCA-PVs carriers to non-carriers. HAEs were manually identified by searching the patients' electronic medical records and classified by CTCAE v5.0. The main endpoint was the incidence rate of any HAE (ie, anaemia, neutropenia, or thrombocytopenia) of grade 2 or more (G ≥ 2).
RESULTS: One hundred and sixty-six patients were included; 95 (57%) had a gBRCA-PV. In total, 162 incident cases of G ≥ 2 HAEs were reported over 255.3 person-years. The incidence rates of G ≥ 2 HAEs were 1003/1000 person-years in gBRCA-PV carriers and 993/1000 person-years in non-carriers. No difference in the incidence rate of G ≥ 2 HAEs emerged comparing gBRCA-PV carriers to non-carriers (crude-incidence rate ratio [IRR]: 1.01; 95% CI: 0.72, 1.43; P = .96), even after adjusting for the type of PARPi (Mantel-Haenszel IRR: 0.99; 95% CI: 0.67, 1.46).
CONCLUSION: Patients with aHGOC and a gBRCA-PV do not experience higher PARPi-related HAEs compared to non-gBRCA-PV carriers, unlike platinum salt-related HAEs.

Keywords:  PARP inhibitors; advanced high-grade ovarian carcinoma; germline BRCA pathogenic variants; hematologic adverse events

DOI:  https://doi.org/10.1093/oncolo/oyae330
Metabolites. 2024 Nov 07. pii: 600. [Epub ahead of print]14(11):

Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers.

Samyukta Sah, Elisabeth M Schwiebert, Samuel G Moore, Ying Liu, David A Gaul, Kristin L M Boylan, Amy P N Skubitz, Facundo M Fernández.

  Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive screening tool combined with ambiguous symptoms hinders these diagnoses. In contrast, screening for cervical cancer via Papanicolaou (Pap) tests is a widespread practice that greatly reduces the cancer's mortality rates. Interestingly, previous studies show evidence of OC cells in Pap tests, suggesting that proteins, and potentially lipids, shed from ovarian tumors end up in the cervix. The goal of this study is to evaluate the practicality of using Pap tests as biospecimens for OC-screening-related metabolomics. Methods: To evaluate the effectiveness of using residual Pap test samples as biospecimens for potential metabolomics work, 29 Pap test samples, collected from women over the age of 50 with normal cytology and no visible blood contamination, were first obtained from the University of Minnesota, with IRB approval. These samples were centrifuged to recover the cell pellets from the supernatants. The cell pellets underwent a biphasic extraction, followed by an RP-LC-MS analysis, while the supernatants underwent two separate extractions and analyses, including RP-LC-MS and HILIC-LC-MS. Non-targeted features were detected in the range of 220-1000 m/z to determine the sensitivity and scope of the various extraction and analytical workflows, as well as evaluating residual Pap test samples as viable metabolomics biospecimens. Results: The biphasic extraction and subsequent RP-LC-MS analysis of the isolated cell pellets from all 29 samples yielded informative, exploratory data, highlighting the potential of using residual Pap test samples as biospecimens for metabolomics, specifically lipidomics, studies. Each sample was analyzed in both the positive and negative ion mode, yielding the detection of 7318 in the positive ion mode and 3733 in the negative ion mode. Using multiple reference libraries, 22.85% and 36.19% of these features were annotated in the positive and negative ion mode, respectively. Among these detected features, 453 unique lipids, representative of 20 different lipid subclasses, were annotated in all 29 samples. Of the various lipid subclasses represented from the detected lipids, ceramides, triacylglycerols, hexosylceramides, and phosphatidylcholines contributed to over half (53.3%) of the detected lipids at 16.2%, 13.0%, 12.8%, and 11.3%, respectively. Conclusions: The detection of these 453 common lipids across all patients establishes a relative lipidome baseline for women over the age of 50 with normal cervical cytology. This exploratory study is the first investigation to utilize residual Pap test samples as biospecimens in a metabolomics/lipidomics workflow.

Keywords:  Papanicolaou (Pap) tests; liquid chromatography (LC); mass spectrometry (MS); ovarian cancer (OC)

DOI:  https://doi.org/10.3390/metabo14110600
Nat Genet. 2024 Nov 26.

Copy number alterations in normal breast tissues revealed by single-cell whole-genome sequencing.

DOI: https://doi.org/10.1038/s41588-024-02018-9
Mol Cancer. 2024 Nov 29. 23(1): 265

Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications.

Hua-Qi Si, Peng Wang, Fei Long, Wei Zhong, Yuan-Dong Meng, Yuan Rong, Xiang-Yu Meng, Fu-Bing Wang.

  Liquid biopsies, in particular, analysis of cell-free DNA, are expected to revolutionize the current landscape of cancer diagnostics and treatment. However, the existing methods for cfDNA-based liquid biopsies for cancer have certain limitations, such as fragment interruption and GC bias, which are likely to be resolved by the emerging Oxford Nanopore Technologies (ONT), characterized by long read-length, fast read-times, high throughput, and polymerase chain reaction-free. In this review, we summarized the current literatures regarding the feasibility and applications of cfDNA-based liquid biopsies using ONT for cancer management, a possible game-changer that we believe is promising in detecting multimodal biomarkers and can be applied in a wide range of oncology utilities including early screening, diagnosis, and treatment monitoring.

Keywords:  Cell-free DNA; Diagnosis; Liquid biopsies; Oncology; Oxford Nanopore Technologies; Personalized medicine

DOI:  https://doi.org/10.1186/s12943-024-02178-6
Nat Rev Clin Oncol. 2024 Nov 28.

Minimal residual disease as a target for liquid biopsy in patients with solid tumours.

Klaus Pantel, Catherine Alix-Panabières.

Metastasis is the leading cause of cancer-related death in patients with solid tumours. Current imaging technologies are not sufficiently sensitive to detect minimal residual disease (MRD; also known as measurable or molecular residual disease) after initial surgery or chemotherapy, pointing to the need for more sensitive tests to detect remaining traces of cancer in the body. Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, has opened a new diagnostic avenue to detect and monitor MRD. Liquid biopsy is already used in clinical decision making for patients with haematological malignancies. Here, we review current knowledge on the use of circulating tumour DNA (ctDNA) to detect and monitor MRD in patients with solid tumours. We also discuss how ctDNA-guided MRD detection and characterization could herald a new era of novel 'post-adjuvant therapies' with the potential to eliminate MRD and cure patients before terminal metastatic disease is evident on imaging.

DOI: https://doi.org/10.1038/s41571-024-00967-y
N Engl J Med. 2024 Nov 28. pii: 10.1056/NEJMc2412661#sa3. [Epub ahead of print]391(21): 2060

Azithromycin to Reduce Mortality.

Maple Goh, Aaron S Kesselheim, Kevin Outterson.

DOI: https://doi.org/10.1056/NEJMc2412661
Nat Rev Genet. 2024 Nov 28.

Genomic landscape of cancer in racially and ethnically diverse populations.

Claire E Thomas, Ulrike Peters.

Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.

DOI: https://doi.org/10.1038/s41576-024-00796-w
Oral Oncol. 2024 Nov 28. pii: S1368-8375(24)00429-9. [Epub ahead of print]160 107111

Deciphering molecular relapse and intra-tumor heterogeneity in non-metastatic resectable head and neck squamous cell carcinoma using circulating tumor DNA.

Grégoire Marret, Constance Lamy, Sophie Vacher, Luc Cabel, Mathieu Séné, Ladidi Ahmanache, Laura Courtois, Zakhia El Beaino, Jerzy Klijanienko, Charlotte Martinat, Nicolas Servant, Choumouss Kamoun, Maral Halladjian, Thierry Bronzini, Cédric Balsat, Jean-François Laes, Aubray Prévot, Sébastien Sauvage, Maxime Lienard, Emmanuel Martin, Bérengère Genin, Nathalie Badois, Maria Lesnik, Antoine Dubray-Vautrin, Olivier Choussy, Wahib Ghanem, Rabah Taouachi, Julien Masliah Planchon, Ivan Bièche, Christophe Le Tourneau, Maud Kamal.

   OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genetic intra-tumor heterogeneity (ITH), which may hinder precision medicine strategies that depend on results from single tumor-biopsy specimens. Treatment response assessment relies on radiologic imaging, which cannot detect minimal residual disease (MRD). We assessed the relevance of circulating tumor DNA (ctDNA) as a biomarker for ITH and MRD in HNSCC.
MATERIALS AND METHODS: We recruited 41 non-metastatic resectable HNSCC patients treated with upfront curative-intent surgery in the prospective biobanking SCANDARE study (NCT03017573). Thirty-one patients (76 %) showed recurrent disease at a median follow-up of 41 months. Targeted next-generation sequencing was performed on resected tumor tissues, as well as on serial blood samples obtained at surgery, within 14 weeks after surgery, at six months and at recurrence.
RESULTS: ctDNA was detected in 21/41 patients at surgery (sensitivity: 51 %; 95 % CI, 35-67 %) and 15/22 patients at recurrence (sensitivity: 68 %; 95 % confidence interval [CI], 45-86 %). Among patients with mutations identified in longitudinal plasma samples, additional mutations missed in tumor tissues were reported in 3/21 patients (14 %), while emerging mutations were reported in 9/21 patients (43 %). In the postoperative surveillance setting, ctDNA-based MRD detection anticipated clinical recurrence with a median lead-time of 9.9 months (interquartile range, 8.0-14.5 months) in 17/27 patients (63 %). When detected within 14 weeks after surgery, MRD correlated with disease recurrence after adjusting for classical prognostic variables (HR = 3.0; 95 % CI, 1.1-7.9; p = 0.03).
CONCLUSIONS: ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients.

Keywords:  Biomarkers; Head and neck squamous cell carcinoma; Liquid biopsy; Next-generation sequencing; Tumor heterogeneity; circulating tumor DNA

DOI:  https://doi.org/10.1016/j.oraloncology.2024.107111
Eur J Clin Invest. 2024 Nov 26. e14363

Genome-wide methylation profiling of maternal cell-free DNA using methylated DNA sequencing (MeD-seq) indicates a placental and immune-cell signature.

Marjolein M van Vliet, Ruben G Boers, Joachim B Boers, Olivier J M Schäffers, Lotte E van der Meeren, Régine P M Steegers-Theunissen, Joost Gribnau, Sam Schoenmakers.

   BACKGROUND: Placental-originated cell-free DNA (cfDNA) provides unique opportunities to study (epi)genetic placental programming remotely, but studies investigating the cfDNA methylome are scarce and usually technologically challenging. Methylated DNA sequencing (MeD-seq) is well compatible with low cfDNA concentrations and has a high genome-wide coverage. We therefore aim to investigate the feasibility of genome-wide methylation profiling of first trimester maternal cfDNA using MeD-seq, by identifying placental-specific methylation marks in cfDNA.
METHODS: We collected cfDNA from nonpregnant controls (female n = 6, male n = 12) and pregnant women (n = 10), first trimester placentas (n = 10), and paired preconceptional and first trimester buffy coats (total n = 20). Differentially methylated regions (DMRs) were identified between pregnant and nonpregnant women. We investigated placental-specific markers in maternal cfDNA, including RASSF1 promoter and Y-chromosomal methylation, and studied overlap with placental and buffy coat DNA methylation.
RESULTS: We identified 436 DMRs between cfDNA from pregnant and nonpregnant women, which were validated using male cfDNA. RASSF1 promoter methylation was higher in maternal cfDNA (fold change 2.87, unpaired t-test p < .0001). Differential methylation of Y-chromosomal sequences could determine fetal sex. DMRs in maternal cfDNA showed large overlap with DNA methylation of these regions in placentas and buffy coats. Sixteen DMRs in maternal cfDNA were specifically found only in placentas. These novel potential placental-specific DMRs were more prominent than RASSF1.
CONCLUSIONS: MeD-seq can detect (novel) genome-wide placental DNA methylation marks and determine fetal sex in maternal cfDNA. Our results indicate a placental and immune-cell contribution to the pregnancy-specific cfDNA methylation signature. This study supports future research into maternal cfDNA methylation.

Keywords:  cell‐free DNA; epigenetics; placenta; pregnancy

DOI:  https://doi.org/10.1111/eci.14363