Genetic Imprinting
And Reproductive Tract Tumors
Imprinting
is the differential expression of a gene or set of genes that is determined by
whether that genetic material was inherited from the mother or from the father.
During the imprinting process, specific genes are methylated so that they can
no longer be transcribed. Therefore, for certain genetic loci, only the
information from one parent is transcriptionally active. When a gene is
maternally imprinted, the gene acquired from the mother is inactive and that
from the father is transcribed. With paternal imprinting, the allele acquired
from the father is inactive. Normal embryonic development requires that one set
of genes be maternally imprinted and a second paternally imprinted. Therefore,
a zygote must not only have a 2n chromosome content but each of the 1n
components must derive from different parents. Several tumors of the
reproductive system have helped us to better understand the process of
imprinting and the consequences of imprinting abnormalities.
Gestational
trophoblastic disease (GTD), dermoid cysts of the ovary and germ-cell tumors
(GCTs) of the testis all display abnormalities in imprinting. GTD and dermoid
tumors contain two sets of chromo- somes from a single parent, so there exists
no opportunity for bipa- rental imprinting. Two sets of maternally imprinted
genes are present in dermoid tumors of the ovary. The result is development of
disorgan- ized fetal tissues without any supporting placenta or fetal
membranes. Conversely, two sets of paternally imprinted genes are present in
GTD. In these cases, dysplastic trophoblast develops, but a fetus does not.
GCTs of the testis have taught different lessons concerning the importance of
imprinting. GCTs that arise in immature and incompletely imprinted cells are
more aggressive than those that arise in fully imprinted germ cells.
Gestational trophoblastic disease
GTD is one
of the earliest reported neoplasms. Hippocrates first described “dropsy” of the
uterus in 400 bc and a 13th century tombstone noted the birth of 365
“children,” half boys and half girls, to the woman buried there. Today GTD,
also called molar pregnancy, retains its leading position in tumor biology as
the most sensitive and curable of all human cancers. The genetic origin of
molar pregnancies has also played a pivotal part in our understanding of the
role of the maternal and paternal genome in embryonic development.
There is a
spectrum of diseases within the GTD classification: hydatidiform mole, either
complete (CHM) or partial (PHM), persistent, nonmetastatic GTD, metastatic
good-prognosis GTD and metastatic poor-prognosis GTD. The latter includes
aggressive tumors known as choriocarcinomas (CC). Of these, CHM and PHM follow
abnormal conceptions and are restricted to women. CC is unique among GTD in
that it can arise from a normal conception, a molar pregnancy or a germ-cell
line. CC in men is exclusively of germ-cell origin (Chapter 40).
CHM and PHM
contain two sets of paternal chromosomes (Fig. 45.1). The former has only
paternally derived genomic DNA. This situation promotes the development of
placental tissues in the absence of fetal tissue development. In PHM, two sets
of paternal chromo- somes are accompanied by a single set of maternal
chromosomes. Again, the paternally imprinted genes are duplicated and placental
overgrowth occurs. Here, maternally imprinted genes are also present and fetal
tissue development is seen.
Complete hydatidiform mole
CHM is the
most common of the GTDs and occurs in about 1 in 1000–1500 pregnancies in
Western countries. It is at least twice as common in Asia but less common in
black races. Extremes of age increase the risk for CHM, with women under 15 and
over 40 at highest risk. Other risk factors include previous history of CHM,
previous miscarriage, maternal balanced chromosomal translocation, professional
occupation and perhaps deficiencies in animal fat and carotene in the diet. A
previously normal pregnancy lowers the risk of CHM.
CHM is
characterized histologically by the presence of large amounts of hydropic
placental villi and no fetal tissue. It presents clinically with delayed menses
and the diagnosis of pregnancy. Pregnancy symptoms such as nausea and vomiting
are often exaggerated because of the high human chorionic gonadotropin (hCG)
production by the abnormal trophoblast. Some patients with CHM will be
hyperthyroid because hCG exhibits some intrinsic thyroid-stimulating activity.
Women with
CHM who want to preserve their fertility are treated by removing the molar
tissue from the uterine cavity (uterine evacuation). Those who do not desire
future fertility may choose hysterectomy. Eighty per cent of CHMs will respond
to these approaches. Those who have persistent disease require chemotherapy and
the vast majority will ultimately be cured. CHM is exquisitely sensitive to
antimetabolite chemotherapy, typically methotrexate with folate rescue.
The unique
genetic origins of CHM were suspected well before the advent of modern
molecular techniques when karyotype analyses revealed that 96% of them were
46XX. Polymerase chain reaction and restriction fragment length polymorphism
(RFLP) analyses have demonstrated that while CHM is always diploid, the
chromosomes are all of paternal origin. Most CHMs arise from fertilization
of an enucleate, or empty egg, with a single 23X sperm. This paternal haplotype
reduplicates and the 46XX karyotype results. The remaining CHMs arise after fertilization
of the enucleate egg with two sperm (dispermy); of these about one-quarter (4%
of the total CHMs) will have a 46XY karyotype. All CHM have maternal
mitochondrial DNA and this confirms that the oocyte cell machinery is involved.
To date, the mechanism by which the egg enucleates is not known. Some
hypothesize that the maternal chromosomes degenerate, others pose that the
female pronucleus is extruded with the polar body (Chapters 4 and 16).
Partial hydatidiform mole
PHM exists
when proliferative villi with hydropic degeneration coexist with a fetus. The
fetus is genetically abnormal and will commonly die by the late first or early
second trimester. The villous hydropic changes seen in PHM are not as
pronounced as those in CHM and may be missed on ultrasonographic examination.
Pathologic examination of the placenta is often necessary to make the
diagnosis. Patients with PHM tend to be older than those with CHM. PHM has a
lower risk of subsequent malignancy than does CHM.
PHM pregnancies are all triploid
and contain two copies of the paternal genome. PHM pregnancies most commonly arise from dispermic
fertilization (diandry). They occasionally occur after fertilization by a
diploid sperm that failed to undergo a first or second reduction division
during meiosis (Chapter 4).
Persistent and metastatic
gestational trophoblastic disease
Persistent
and metastatic GTD are typically preceded by CHM. They occasionally follow PHM
or even normal pregnancies. Persistent GTD can invade the uterus or metastasize
to liver, lung and brain. Even metastatic disease has a very high cure rate
with appropriate treatment.
Genetic
study of neoplastic trophoblastic tissue is very important to the patient because
gestational tumors have a better than 90% cure rate whereas nongestational
tumors with trophoblastic differentiation are essentially lethal.
Dermoid tumors
Benign
ovarian teratomas, also known as dermoids, arise from “par-
thenogenetic” activation of premeiotic oocytes. Parthenogenetic activation of
the oocyte stimulates oocyte mitosis in the absence of the male pronucleus and
its accompanying DNA. Parthenogenetic activation can be induced in vitro by
a variety of methods, including chemical and electrical exposure. The stimuli
that drive parthenogenesis in the formation of ovarian teratomas are not known.
All the chromosomes in an ovarian dermoid tumor are maternally derived and,
therefore, maternally imprinted. The tumors are characterized by disorganized
overgrowth of many of the cell types normally seen in fetuses. This includes
hair, bone, cartilage, adipose tissue and glandular derivatives (Fig. 45.2).
Ovarian
dermoid tumors arise from more mature germ cells than the other female GCTs
(Chapter 42). Like other GCTs, the molecular event(s) that lead to activation
of the germ cells can occur in utero, and indeed dermoid tumors have
been detected in the fetus and newborn infant.
GCTs of the testis
Spermatocytic
seminomas are unique among the GCTs of the testis in that they are found in
older men and are typically slow-growing (Chapter 40). This less aggressive
behavior may occur because spermatocytic seminomas arise from mature
spermatogonia rather than spermatogonial stem cells. During the development of
spermatozoa, the diploid (biparental) spermatogonial stem cell must undergo
reduction division to the haploid state. It is equally important that the DNA
in these haploid cells be completely uniparental. If this occurs, appropriate
paternally imprinted DNA will be transmitted during fertilization. Imprinting
appears to occur during spermatocyte maturation some time after the second
meiotic division halves the chromosome number. When neoplastic transformation
occurs in immature testicular germ cells, the biparental imprinting of the
cells preserves pluripotentiality and allows the development of less
differentiated, aggressive tumors with embryonal or trophoblastic components.
When transformation occurs in more mature and fully imprinted spermatogonium, the
tumors are less aggressive (spermatocytic seminomas).
