Pathogenesis of Placental Site Trophoblastic Tumor May Require the Presence of a Paternally Derived X Chromosome

Abstract

SUMMARY:Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of intermediate trophoblasts that invades the myometrium at the placental site after a pregnancy. Less than 100 cases have been reported. Information of the sex assignment of the antecedent gestation is available in 21 cases: 18 of these were female. To explore this interesting phenomenon, we have determined the sex chromosome composition of the tumor tissue preserved in paraffin blocks for five new cases of this condition. The last documented gestational event included a normal vaginal delivery of female infants in three cases, normal vaginal delivery of an infant of unknown sex in one case and a molar gestation in one case. Using the X-linked human androgen receptor (AR) gene as a polymorphic marker, we showed that in all five cases the tumor had a likely XX chromosomal composition; and in four cases it was possible to determine that one of the X chromosomes was of paternal origin. In one case, the paternal X chromosome showed no polymorphism to either maternal X chromosomes. In addition, sensitive semi-nested PCR failed to show a human Y chromosome element in any of the five cases of PSTT. Overall, of 21 cases from the literature and 5 cases of ours, 89% (23 of 26) showed an XX genomic composition in PSTT, either by history or genetic analysis. These results suggest that most PSTT were derived from the antecedent female conceptus and were likely to have possessed a functional paternal X chromosome. Methylation status analysis at the AR locus was performed in the three PSTT in which the paternal X chromosome was identifiable. In two cases, the paternal AR locus was hypomethylated while the corresponding maternal locus was hypermethylated. The methylation status of other loci was not investigated. Collectively, sex chromosome analysis of five cases of PSTT with literature support suggests a unique genetic basis for the development of PSTT that involves the paternal X chromosome. Although largely speculative, an active paternal X chromosome may be of importance in the pathogenesis of PSTT. (Lab Invest 2000, 80:965-972).D uring conception, tissue having paternallyderived genetic material is implanted in the female uterus. Rarely, this event leads to the development of a disease in the mother in the form of gestational trophoblastic disease (GTD). GTD includes some entities characterized by distinct unique genetic modes of pathogenesis which have been recognized for long time (Kajii and Ohama, 1977;Szulman, 1984): in complete hydatidiform moles, more than 90% of the proliferative trophoblasts have a 46, XX diploid pattern, all derived from the sperm (androgenesis). In partial moles, the karyotype is triploid in most cases (eg, 69, XXY), resulting from fertilization of an egg with one or two sperm. In fact, triploid gestations in which there is no duplication of the paternal chromosomes do not have trophoblastic hyperplasia and do not meet the histologic criteria of molar gestation (Jacobs et al, 1982). Therefore, duplication of the pat...

Absence of Y chromosome in human placental site trophoblastic tumor

“…6,7 We have previously noted through literature reviews that a majority of the tumors were preceded by a female gestational event and our pilot molecular investigation suggested that the tumorigenesis likely requires the presence of a paternally derived X chromosome in the tumor genome. 8 We now present an analysis of a larger series of cases to confirm these earlier observations.…”

“…8 Since then, additional case reports of placental site trophoblastic tumor have been published and again a female antecedent pregnancy was documented in 12 out of 14 new cases. [13][14][15] One cell line from a placental site trophoblastic tumor was established and confirmed by karyotyping to have XX genome.…”

Comparative genomic hybridization study of placental site trophoblastic tumour: a report of four cases

“…The presence of hybridization signal to a small number of Y-chromosomes likely represents a nonspecific finding, which has been observed a similar study 7 and our previous study using nested genomic PCR failed to demonstrate Y-chromosome-specific sequences in tumour cells of these cases. 4 Histologically, the two tumours with abnormal CGH output (cases 1 and 2) showed no significant morphological differences from the other two tumours having a balanced CGH profile (cases 3 and 4). Clinical follow-up information was available in two patients (cases 2 and 4) who were alive without evidence of tumour recurrence.…”

“…Although our understanding of the pathogenesis of GTDs is limited, an emerging body of data has suggested that abnormal genomic composition and altered epigenic regulation by genomic imprinting appear to play important roles in the development of GTDs. 4,[8][9][10] It is interesting that, comparable with the proliferative spectrum of GTDs, chromosomal alterations detectable by CGH increase as the lesion becomes more proliferative and aggressive. At the benign end, hydatidiform moles display balanced CGH profiles 11 and they carry the least proliferative potential, compatible with a non-neoplastic process.…”

“…Although morphologic and clinical studies are not uncommon in case report or small series, molecular and genetic studies of PSTT are quite limited. 2,3,4 Comparative genomic hybridization (CGH) is a molecular approach to reach the genome for imbalanced genetic material. 5,6 Labelled genomic test DNA, prepared from tumour sample, is mixed with differently labelled control DNA obtained from normal reference cells.…”