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Genetic Imprinting And Reproductive Tract Tumors

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.
 Genetic Imprinting And Reproductive Tract Tumors, Imprinting, Gestational trophoblastic disease, Complete hydatidiform mole, Partial hydatidiform mole, Persistent and metastatic gestational trophoblastic disease, Dermoid tumors, GCTs of the testis,
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).

Genetic Imprinting And Reproductive Tract Tumors, Imprinting, Gestational trophoblastic disease, Complete hydatidiform mole, Partial hydatidiform mole, Persistent and metastatic gestational trophoblastic disease, Dermoid tumors, GCTs of the testis,

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).