Publications
121 results found
McMahon L, Maher G, Joyce C, et al., 2023, When to consult a geneticist specialising in gestational trophoblastic disease, Gynecologic and Obstetric Investigation, ISSN: 0378-7346
Background: Gestational trophoblastic disease comprises hydatidiform moles and a rare group of malignancies that derive from trophoblasts. Although there are typical morphological features that may distinguish hydatidiform moles from non-molar products of conception, such features are not always present, especially at early stages of pregnancy. Furthermore, mosaic/chimeric pregnancies and twin pregnancies make pathological diagnosis challenging while trophoblastic tumours can also pose diagnostic problems in terms of their gestational or non-gestational origin. Objectives: To show that ancillary genetic testing can be used to aid diagnosis and clinical management of GTD. Methods: Each author identified cases where genetic testing, including short tandem repeat (STR) genotyping, ploidy analysis, next generation sequencing and immunostaining for p57, the product of the imprinted gene CDKN1C, facilitated accurate diagnosis and improved patient management. Representative cases were chosen to illustrate the value of ancillary genetic testing in different scenarios. Outcome: Genetic analysis of placental tissue can aid in determining the risk of developing gestational trophoblastic neoplasia, facilitating discrimination between low risk triploid (partial) and high risk androgenetic (complete) moles, discriminating between a hydatidiform mole twinned with a normal conceptus and a triploid conception and identification of androgenetic/biparental diploid mosaicism. STR genotyping of placental tissue and targeted gene sequencing of patients can identify women with an inherited predisposition to recurrent molar pregnancies. Genotyping can distinguish gestational from non-gestational trophoblastic tumours using tissue or circulating tumour DNA, and can also identify the causative pregnancy which is the key prognostic factor for placental site and epithelioid trophoblastic tumours. Conclusions and Outlook: STR genotyping and P57 immunostaining have been invaluable to the managem
Slim R, Fisher R, Milhavet F, et al., 2022, Biallelic <i>NLRP7</i> variants in patients with recurrent hydatidiform mole: A review and expert consensus, HUMAN MUTATION, Vol: 43, Pages: 1732-1744, ISSN: 1059-7794
- Author Web Link
- Cite
- Citations: 4
Maher G, Fisher RA, Kaur B, et al., 2022, Sensitive screening of single nucleotide polymorphisms in cell free DNA for diagnosis of gestational tumours, npj Genomic Medicine, Vol: 7, Pages: 1-8, ISSN: 2056-7944
Tumours expressing human chorionic gonadotropin (hCG), the majority of which are difficult to biopsy due to their vascularity, have disparate prognoses depending on their origin. As optimal management relies on accurate diagnosis, we aimed to develop a sensitive cell free DNA (cfDNA) assay to non-invasively distinguish between cases of gestational and non-gestational origin. Deep error-corrected Illumina sequencing of 195 common single nucleotide polymorphisms (SNPs) in cfDNA and matched genomic DNA from 36 patients with hCG-secreting tumours (serum hCG 5 to 3,042,881 IU/L) and 7 controls with normal hCG levels (≤ 4 IU/L) was performed. cfDNA from confirmed gestational tumours with hCG levels ranging from 1,497 to 700,855 IU/L had multiple (n ≥12) ‘non-host’ alleles (i.e. alleles of paternal origin). In such cases the non-host fraction of cfDNA ranged from 0.3% - 40.4% and correlated with serum hCG levels. At lower hCG levels the ability to detect non-host cfDNA was variable, with the detection limit dependent on the type of causative pregnancy. Patients with non-gestational tumours were identifiable by the absence of non-host cfDNA, with copy number alterations detectable in the majority of cases. Following validation in a larger cohort, our sensitive assay will enable clinicians to better inform patients, for whom biopsy is inappropriate, of their prognosis and provide optimum management.
Maher GJ, Fisher RA, Kaur B, et al., 2022, Sensitive screening of cell free DNA to determine the origin of trophoblastic tumours, Publisher: SPRINGERNATURE, Pages: 97-98, ISSN: 1018-4813
Bobdiwala S, Harvey R, Abdallah Y, et al., 2022, The potential use of urinary hCG measurements in the management of pregnancies of unknown location, HUMAN FERTILITY, Vol: 25, Pages: 256-263, ISSN: 1464-7273
Fisher RA, 2021, Genetics of gestational trophoblastic disease, Best Practice and Research: Clinical Obstetrics and Gynaecology, Vol: 74, Pages: 29-41, ISSN: 1521-6934
The abnormal pregnancies complete and partial hydatidiform mole are genetically unusual, being associated with two copies of the paternal genome. Typical complete hydatidiform moles (CHMs) are diploid and androgenetic, while partial hydatidiform moles (PHMs) are diandric triploids. While diagnosis can usually be made on the basis of morphology, ancillary techniques that exploit their unusual genetic origin can be used to facilitate diagnosis. Genotyping and p57 immunostaining are now routinely used in the differential diagnosis of complete and partial hydatidiform moles, for investigating unusual mosaic or chimeric products of conception with a molar component and identifying the rare diploid, biparental HMs associated with an inherited predisposition to molar pregnancies. Genotyping also plays an important role in the differential diagnosis of gestational and non-gestational trophoblastic tumours and identification of the causative pregnancy where tumours are gestational. Recent developments include the use of cell-free DNA for non-invasive diagnosis of these conditions.
Lin LH, Maesta I, St Laurent JD, et al., 2021, Distinct microRNA profiles for complete hydatidiform moles at risk of malignant progression, AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, Vol: 224, ISSN: 0002-9378
- Author Web Link
- Cite
- Citations: 14
Savage P, Winter M, Parker V, et al., 2020, Demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 127, Pages: 1102-1107, ISSN: 1470-0328
- Author Web Link
- Cite
- Citations: 12
Frijstein MM, Lok CAR, van Trommel NE, et al., 2020, Lung metastases in low-risk gestational trophoblastic neoplasia: a retrospective cohort study, Publisher: WILEY, Pages: 389-395, ISSN: 1470-0328
- Author Web Link
- Cite
- Citations: 16
Sava G, Fan H, Fisher R, et al., 2020, ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942., Oncogene, Vol: 39, Pages: 651-663, ISSN: 0950-9232
The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was up-regulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.
Russell JC, Niemann I, Sebire NJ, et al., 2019, UPDATE ON UK OUTCOMES IN TWIN PREGNANCIES WITH COMPLETE HYDATIDIFORM MOLE AND NORMAL CO-TWIN: A RETROSPECTIVE NATIONAL COHORT STUDY IN 153 NEW CASES, Publisher: BMJ PUBLISHING GROUP, Pages: A164-A165, ISSN: 1048-891X
Savage P, Monk D, Hernandez Mora JR, et al., 2019, A case of intraplacental gestational choriocarcinoma; characterised by the methylation pattern of the early placenta and an absence of driver mutations, BMC CANCER, Vol: 19, ISSN: 1471-2407
- Author Web Link
- Cite
- Citations: 12
Froeling FEM, Ramaswami R, Papanastasopoulos P, et al., 2019, Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours, BRITISH JOURNAL OF CANCER, Vol: 120, Pages: 587-594, ISSN: 0007-0920
- Author Web Link
- Cite
- Citations: 33
Earp KE, Hancock BW, Short D, et al., 2019, Do we need post-pregnancy screening with human chorionic gonadotrophin after previous hydatidiform mole to identify patients with recurrent gestational trophoblastic disease?, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 234, Pages: 117-119, ISSN: 0301-2115
- Author Web Link
- Cite
- Citations: 1
Frijstein MM, Lok CAR, Short D, et al., 2019, The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia, EUROPEAN JOURNAL OF CANCER, Vol: 109, Pages: 162-171, ISSN: 0959-8049
- Author Web Link
- Cite
- Citations: 27
Carson JC, Hoffner L, Conlin L, et al., 2018, Diploid/triploid mixoploidy: A consequence of asymmetric zygotic segregation of parental genomes, AMERICAN JOURNAL OF MEDICAL GENETICS PART A, Vol: 176, Pages: 2720-2732, ISSN: 1552-4825
- Author Web Link
- Cite
- Citations: 14
Ghorani E, Kaur B, Fisher RA, et al., 2017, Pembrolizumab is effective for drugresistant gestational trophoblastic neoplasia, Lancet, Vol: 390, Pages: 2343-2345, ISSN: 0140-6736
Lavoie J-M, Alcaide M, Fisher RA, et al., 2017, Targeted Error-Suppressed Detection of Circulating Paternal DNA to Establish a Diagnosis of Gestational Trophoblastic Neoplasm, JCO PRECISION ONCOLOGY, Vol: 1
Zhao S, Sebire NJ, Kaur B, et al., 2016, Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance., Gynecologic Oncology, ISSN: 1095-6859
OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p<0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles.
Tyebally S, Ghorani E, Kaur B, et al., 2016, A case of progressive breathlessness post partum, Thorax, Vol: 71, Pages: 871-872, ISSN: 1468-3296
Sebire NJ, May PC, Kaur B, et al., 2016, Abnormal Villous Morphology Mimicking a Hydatidiform Mole Associated with Paternal Trisomy of Chromosomes 3,7,8 and Unipaternal Disomy of Chromosome 11., Diagnostic Pathology, Vol: 11, ISSN: 1746-1596
BackgroundPregnancies affected by non-molar chromosomal abnormality may sometimes demonstrate abnormal chorionic villous morphology that is similar to partial hydatidiform mole. Determination of the underlying aetiology may be difficult in such cases.Case PresentationThis report describes a case referred to the regional trophoblastic disease unit as a possible hydatidiform mole that demonstrated both villous dysmorphology and abnormal p57KIP2 expression. Molecular genotyping revealed that while most chromosomes in the villous tissue were diploid and biparental, chromosomes 3, 7 and 8 were trisomic with an additional paternally derived chromosome. In contrast chromosome 11 showed uniparental disomy of paternal origin a situation more usually associated with complete hydatidiform moles. This unusual case highlights that exceptions may occur to the general rules of both histological morphology and immunoprofile, and that these can be resolved by detailed molecular genetic investigations.ConclusionThe findings confirm that trisomic pregnancies may demonstrate morphological villous features similar to hydatidiform mole, and that loss of p57KIP2 expression occurs due to an absence of maternally transcribed genes on chromosome 11 and can therefore be independent of androgenetic complete hydatidiform mole.
Fisher RA, Openshaw M, Harvey R, et al., 2015, Circulating cell free DNA in the diagnosis of trophoblastic tumors, EBioMedicine, Vol: 4, Pages: 146-152, ISSN: 2352-3964
Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of humanchorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosisis important for appropriate clinical management. However, a histopathological diagnosis is not alwaysavailable. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma ofwomen with GTN for use as a “liquid biopsy” in patients without histopathological diagnosis. cfDNA was preparedfrom the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknownorigin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from thetumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patientswith GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molarconception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instabilityand loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTNand can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases withouthistopathological diagnosis
Sanchez-Delgado M, Martin-Trujillo A, Tayama C, et al., 2015, Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting, PLOS Genetics, Vol: 11, ISSN: 1553-7390
Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorderusually associated with mutations of the NLRP7 gene. It is characterized by HM withexcessive trophoblastic proliferation, which mimics the appearance of androgenetic molarconceptuses despite their diploid biparental constitution. It has been proposed that the phenotypesof both types of mole are associated with aberrant genomic imprinting. However nosystematic analyses for imprinting defects have been reported. Here, we present thegenome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7defective molar tissues. We observe total paternalization of all ubiquitous and placentaspecificdifferentially methylated regions (DMRs) in four androgenetic moles; namely gain ofmethylation at paternally methylated loci and absence of methylation at maternally methylatedregions. The methylation defects observed in five RHM biopsies from NLRP7 defectivepatients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs fromtwo sisters with the same missense mutations, as well as consecutive RHMs from oneaffected female show subtle allelic methylation differences, suggesting inter-RHM variation.These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involvedin imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent withimprinting in the placenta, of which we confirm 22 as novel maternally methylated loci.These observations strongly suggest that the molar phenotypes are due to defective placenta-specificimprinting and over-expression of paternally expressed transcripts, highlightingthat maternal-effect mutations of NLRP7 are associated with the most severe form ofmulti-locus imprinting defects in humans.
Sunde L, Lund H, J Sebire N, et al., 2015, Paternal Hemizygosity in 11p15 in Mole-like Conceptuses: Two Case Reports., Medicine (Baltimore), Vol: 94, ISSN: 0025-7974
Hydatidiform mole is an abnormal human pregnancy characterized by the fetus being absent or nonviable, and the chorionic villi being vesicular and with trophoblastic hyperplasia. Most often, the mole phenotype is seen in conceptuses with an excess of paternally inherited genome set(s) relative to maternally inherited genome set(s), suggesting that the phenotype is caused by an excess of genome with a paternal imprinting pattern. However, it is unknown if correct parental origin of every imprinted gene is crucial for normal early differentiation or if abnormal parental imprinting of only one, or some, gene(s) can cause the mole phenotype.Two conceptuses included in the Danish Mole Project stood out since they presented with vesicular chorionic villi and without signs of fetal differentiation, and had apparently biparental diploid genomes, and no mutations in NLRP7 or KHDC3L were detected in the mothers. These conceptuses were subjected to a centralized histopathological revision and their genetic complements were scrutinized using fluorescence in situ hybridization, and DNA-marker and array comparative genomic hybridization analyses. Both conceptuses showed dysmorphic chorionic villi with some similarities to hydatidiform moles; however, no definite florid trophoblast hyperplasia was observed. Both conceptuses showed paternal hemizygosity of 11pter-11p15.4, most likely in nonmosaic state.Our findings suggest that the product of one (or a few) maternally expressed gene(s) on the tip of chromosome 11 is necessary for normal early embryonic differentiation. However, since the present two cases did not exhibit all features of hydatidiform moles, it is likely that abnormal parental imprinting of genes in other regions contribute to the phenotype of a hydatidiform mole.
Eagles N, Sebire NJ, Short D, et al., 2015, Risk of recurrent molar pregnancies following complete and partial hydatidiform moles, HUMAN REPRODUCTION, Vol: 30, Pages: 2055-2063, ISSN: 0268-1161
- Author Web Link
- Cite
- Citations: 39
Kaur B, Short D, Fisher RA, et al., 2015, Atypical Placental Site Nodule (APSN) and Association With Malignant Gestational Trophoblastic Disease; A Clinicopathologic Study of 21 Cases, INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, Vol: 34, Pages: 152-158, ISSN: 0277-1691
- Author Web Link
- Cite
- Citations: 33
Aghajanova L, Mahadevan S, Altmaee S, et al., 2015, No evidence for mutations in <i>NLRP7</i>, <i>NLRP2</i> or <i>KHDC3L</i> in women with unexplained recurrent pregnancy loss or infertility, HUMAN REPRODUCTION, Vol: 30, Pages: 232-238, ISSN: 0268-1161
- Author Web Link
- Cite
- Citations: 11
Fisher RA, Tommasi A, Short D, et al., 2014, Clinical utility of selective molecular genotyping for diagnosis of partial hydatidiform mole; a retrospective study from a regional trophoblastic disease unit, JOURNAL OF CLINICAL PATHOLOGY, Vol: 67, Pages: 980-984, ISSN: 0021-9746
- Author Web Link
- Cite
- Citations: 25
Petts G, Fisher RA, Short D, et al., 2014, Histopathological and immunohistochemical features of early hydatidiform mole in relation to subsequent development of persistent gestational trophoblastic disease, Journal of Reproductive Medicine, Vol: 59, Pages: 213-220, ISSN: 0024-7758
OBJECTIVE: To examine histomorphological and immunohistochemical findings in hydatidiform moles to determine whether any features can reliably predict clinical behavior. STUDY DESIGN: Blinded semiquantitative review of histological and immunohistochemical findings in cases of partial hydatidiform mole (PHM) (N = 50) and complete hydatidiform mole (CHM) which either spontaneously resolved (N=50) or required chemotherapy (N=50). Immunostains assessed included MLH1, MSH2, nm23, TERT, p53, EGFR, and CerbB2 based on previous data. RESULTS: There were marked morphological differences in various criteria between CHMs and PHMs, including the proportion of villi with abnormal trophoblast hyperplasia (29% vs. 6%, respectively). However, there were no significant differences in any morphological parameters between CHMs that spontaneously resolved and those that subsequently required chemotherapy. Similarly, there were no clinically useful differences regarding any immunostaining scores between CHM groups. CONCLUSION: Neither morphological nor immunohistochemical features can reliably predict subsequent requirement of chemotherapy in CHMs.
Petts G, Fisher RA, Short D, et al., 2014, Histopathological and Immunohistochemical Features of Early Hydatidiform Mole in Relation to Subsequent Development of Persistent Gestational Trophoblastic Disease, JOURNAL OF REPRODUCTIVE MEDICINE, Vol: 59, Pages: 213-220, ISSN: 0024-7758
- Author Web Link
- Cite
- Citations: 8
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.