Imprinting
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 chromosomes from a single parent, so there exists no opportunity for biparental imprinting. Two sets of maternally imprinted genes are present in dermoid tumors of the ovary. The result is development of disorganized 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 chromosomes 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).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
