Study of the Genetic and Epigenetic Causes of Recurrent Hydatidiform Moles

Conditions:Cancer, Dermatology
Therapuetic Areas:Dermatology / Plastic Surgery, Oncology
Age Range:Any
Start Date:December 1998
End Date:January 2020
Contact:Rajesh Ramakrishnan, PhD

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Genetic Studies in Gestational Trophoblastic Disease

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.

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.

Inclusion Criteria:

- Personal or family history of recurrent moles or a sporadic mole

- Presence of a mutation in NLRP7

Exclusion Criteria:
We found this trial at
1200 Moursund Street
Houston, Texas 77030
(713) 798-4951
Principal Investigator: Ignatia B Van den Veyver, MD
Phone: 713-798-4914
Baylor College of Medicine Baylor College of Medicine in Houston, the only private medical school...
Houston, TX
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