Clinical trial NCT01008501: Study of the Genetic and Epigenetic Causes of Recurrent Hydatidiform Moles
Official title: Genetic Studies in Gestational Trophoblastic Disease
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Hydatidiform Moles
Keywords: hydatidiform moles
complete hydatidiform moles
partial hydatidiform moles
Molar pregnancy
NLRP7
pregnancy wastage
imprinting
sporadic hydatidiform moles
recurrent hydatidiform moles
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
First posted: 2009-11-05
Enrollment: 100
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals who have had sporadic or recurrent hydatidiform moles and their first degree relatives. Sometimes additional family members are also enrolled.

Brief summary: The researchers' laboratory is studying a rare class of highly recurrent hydatidiform moles. These are usually complete hydatidiform moles (CHM), but sometimes they are partial hydatidiform moles PHM). With sporadic moles, the difference between CHMs and PHMs is that with CHMS, there is not typically an embryo or fetus at the time of diagnosis but with a PHM there may be a fetus. Also, CHMs have 46 chromosomes in each cell. While this is the number of chromosomes that should be found, the problem is that all the chromosomes come from the father. Normally, half the chromosomes should come from the mother and half should come from the father. Unlike CHMs, PHMs have 69 chromosomes. This means that PHMs have three copies of each chromosome when they should only have two. The extra copy comes from the father.

The researchers' study focuses on moles that are genetically different from these sporadic moles in that they have 23 chromosomes from the mother and 23 chromosomes from the father - just like a normally developing pregnancy. These are called biparental moles because the mutation that causes the mole comes from both parents. This mutation occurs in a gene called NLRP7. The researchers' team is working to understand how mutations in NLRP7 leads to CHMs and how these mutations may lead to other types of pregnancy loss. The researchers are also trying to discover other genetic and epigenetic factors that may lead to moles.

Detailed description: Hydatidiform mole (HM) is the product of an aberrant human pregnancy in which there is abnormal embryonic development and abnormal proliferation of placental villi. The incidence of HM varies between ethnic groups, and occurs in 1 in every 1500 pregnancies in the USA. All HM cases are sporadic except for extremely rare familial cases. The exact mechanisms leading to molar pregnancies are not known. Hydatidiform moles are classified based on histology and karyotype data into two types:

complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM). The complete forms are characterized by general trophoblastic proliferation and absence of an embryo and amniotic membranes. In most of the cases, CHM have a diploid genome, and are androgenetic with two identical sets of paternal chromosomes. Partial hydatidiform moles are characterized by focal trophoblastic proliferation. Embryos and amniotic membranes are usually present in these molar pregnancies. Partial hydatidiform moles are mostly triploid with two sets of paternal chromosomes and one set of maternal chromosomes. The comparison of findings in androgenetic CHM and PHM indicate that both maternally (under) expressed and paternally (over) expressed genes play a role in the pathophysiology of molar pregnancies. Very few genetic studies have been performed on molar pregnancies or the patients who carry these pregnancies. A few studies have looked at the over- or underexpression of genes that may play a role in the progression or invasiveness of hydatidiform moles; however none have addressed the underlying genetic etiology. We have been able to study an inbred family of which several female members have had recurrent hydatidiform moles and have now genetically mapped the defective gene responsible for the molar pregnancies in this family. We then worked towards refined characterization of the genetic locus containing the mutated gene and analysis of candidate genes in this region for mutations leading to molar pregnancy. Because the hydatidiform moles in these patients have abnormal genetic imprinting, we believe that this candidate gene is important for establishment of genetic imprinting in the maternal germline. Recently, another group of investigators studying this condition identified mutations in a gene, NALP7 (now renamed to NLRP7), in some of the affected women. We confirmed this in other subjects studied by us. This is the first identified gene, but there is genetic heterogeneity and other genes still remain to be found. In addition, the normal function of this gene in reproduction and how it leads to recurrent moles when mutated remains to be determined. To study both of these, it will be very important to collect as many molar pregnancy tissue samples as possible, as well as blood samples and/or other non-invasively obtained samples, such as buccal swabs and saliva, from affected patients and their families. Recent evidence suggests that mutations in NLRP7 might cause other forms of reproductive failure, such as triploid spontaneous abortions. It has further been proposed that the mutation status of NLRP7 in women with recurrent reproductive loss is an important predictor of the outcome of Assisted Reproductive Technologies. Therefore, we are carrying out mutation analysis of NLRP2 and NLRP7 in women with unexplained infertility and other forms of reproductive failure.

Eligibility criteria: Inclusion Criteria:

* Personal or family history of recurrent moles or a sporadic mole
* Presence of a mutation in NLRP7

Exclusion Criteria:

* None

Primary outcomes:
measure: Identifying the change in the genetic information that causes recurrent hydatidiform moles.
timeFrame: Through study completion, an average of 15 years.
measure: Identifying the changes in the genetic information that cause different forms of unexplained reproductive failure
timeFrame: Through study completion, an average of 15 years.
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Ignatia B Van den Veyver, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kou YC, Shao L, Peng HH, Rosetta R, del Gaudio D, Wagner AF, Al-Hussaini TK, Van den Veyver IB. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod. 2008 Jan;14(1):33-40. doi: 10.1093/molehr/gam079. Epub 2007 Nov 26.
citation: Van den Veyver IB, Al-Hussaini TK. Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring. Hum Reprod Update. 2006 May-Jun;12(3):233-42. doi: 10.1093/humupd/dmk005. Epub 2006 Mar 15.
citation: Panichkul PC, Al-Hussaini TK, Sierra R, Kashork CD, Popek EJ, Stockton DW, Van den Veyver IB. Recurrent biparental hydatidiform mole: additional evidence for a 1.1-Mb locus in 19q13.4 and candidate gene analysis. J Soc Gynecol Investig. 2005 Jul;12(5):376-83. doi: 10.1016/j.jsgi.2005.02.011.
citation: Al-Hussaini TK, Abd el-Aal DM, Van den Veyver IB. Recurrent pregnancy loss due to familial and non-familial habitual molar pregnancy. Int J Gynaecol Obstet. 2003 Nov;83(2):179-86. doi: 10.1016/s0020-7292(03)00209-1.
citation: Saxena A, Frank D, Panichkul P, Van den Veyver IB, Tycko B, Thaker H. The product of the imprinted gene IPL marks human villous cytotrophoblast and is lost in complete hydatidiform mole. Placenta. 2003 Sep-Oct;24(8-9):835-42. doi: 10.1016/s0143-4004(03)00130-9.
citation: Van den Veyver IB, Norman B, Tran CQ, Bourjac J, Slim R. The human homologue (PEG3) of the mouse paternally expressed gene 3 (Peg3) is maternally imprinted but not mutated in women with familial recurrent hydatidiform molar pregnancies. J Soc Gynecol Investig. 2001 Sep-Oct;8(5):305-13. doi: 10.1016/s1071-5576(01)00129-0.
citation: Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den Veyver I, Slim R. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum Mol Genet. 1999 Apr;8(4):667-71. doi: 10.1093/hmg/8.4.667.
citation: Qian J, Deveault C, Bagga R, Xie X, Slim R. Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations. Hum Mutat. 2007 Jul;28(7):741. doi: 10.1002/humu.9498.
citation: Slim R, Mehio A. The genetics of hydatidiform moles: new lights on an ancient disease. Clin Genet. 2007 Jan;71(1):25-34. doi: 10.1111/j.1399-0004.2006.00697.x.
citation: Djuric U, El-Maarri O, Lamb B, Kuick R, Seoud M, Coullin P, Oldenburg J, Hanash S, Slim R. Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation. Hum Genet. 2006 Oct;120(3):390-5. doi: 10.1007/s00439-006-0192-3. Epub 2006 Jul 28.
citation: Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006 Mar;38(3):300-2. doi: 10.1038/ng1740. Epub 2006 Feb 5.
citation: Fisher RA, Hodges MD, Newlands ES. Familial recurrent hydatidiform mole: a review. J Reprod Med. 2004 Aug;49(8):595-601.
citation: Zhao J, Moss J, Sebire NJ, Cui QC, Seckl MJ, Xiang Y, Fisher RA. Analysis of the chromosomal region 19q13.4 in two Chinese families with recurrent hydatidiform mole. Hum Reprod. 2006 Feb;21(2):536-41. doi: 10.1093/humrep/dei357. Epub 2005 Oct 20.
citation: Fisher RA, Hodges MD, Rees HC, Sebire NJ, Seckl MJ, Newlands ES, Genest DR, Castrillon DH. The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum Mol Genet. 2002 Dec 15;11(26):3267-72. doi: 10.1093/hmg/11.26.3267.
citation: van der Smagt JJ, Scheenjes E, Kremer JA, Hennekam FA, Fisher RA. Heterogeneity in the origin of recurrent complete hydatidiform moles: not all women with multiple molar pregnancies have biparental moles. BJOG. 2006 Jun;113(6):725-8. doi: 10.1111/j.1471-0528.2006.00929.x.
citation: Mahadevan S, Wen S, Balasa A, Fruhman G, Mateus J, Wagner A, Al-Hussaini T, Van den Veyver IB. No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles. Prenat Diagn. 2013 Dec;33(13):1242-7. doi: 10.1002/pd.4239. Epub 2013 Oct 4.
citation: Mahadevan S, Wen S, Wan YW, Peng HH, Otta S, Liu Z, Iacovino M, Mahen EM, Kyba M, Sadikovic B, Van den Veyver IB. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation. Hum Mol Genet. 2014 Feb 1;23(3):706-16. doi: 10.1093/hmg/ddt457. Epub 2013 Sep 18.