Gestational trophoblastic disease: understanding the molecular mechanisms of placental tumours

Abstract

Gestational trophoblastic disease (GTD) describes a group of rare benign and cancerous lesions originating from the trophoblast cells of the placenta. These neoplasms are unconventional entities, being one of the few instances in which cancer develops from the cells of another organism, the foetus. Although this condition was first described over 100 years ago, the specific genetic and non-genetic drivers of this disease remain unknown to this day. However, recent findings have provided valuable insights into the potential mechanisms underlying this rare condition. Unlike previous reviews focused primarily on the clinical and diagnostic aspects of disease development, this Review consolidates the latest research concerning the role of genetics, epigenetics and microRNAs in the initiation and progression of GTD. By examining GTD from a molecular perspective, this Review provides a unique framework for understanding the pathogenesis and progression of this rare disease.

Keywords: Choriocarcinoma; Gestational trophoblastic disease; Gestational trophoblastic neoplasia; Molar pregnancy; Placental tumour.

Fig. 1.

Gestational trophoblastic disease (GTD) classification. GTD encompasses a spectrum of benign and malignant lesions in the placenta. Benign lesions include atypical placental site nodule (APSN) and molar pregnancies [partial hydatidiform moles (PHMs) and complete hydatidiform moles (CHMs)]. Malignant gestational lesions, also known as gestational trophoblastic neoplasia (GTN), include invasive moles, choriocarcinoma (CC), placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Whereas all invasive moles follow a molar pregnancy, other cancers can be of molar or non-molar origin. The arrow indicates metastasis.

Fig. 2.

Genetic origins of different types of hydatidiform mole. (A) Almost all triploid PHMs form as a result of fertilisation by two sperms (dispermy). (B) Top: the majority of androgenetic CHMs are homozygous. They arise as a consequence of monospermic fertilisation where maternal chromosomes are lost either before or after conception, followed by duplication of paternal DNA. Bottom: in some cases, heterozygous CHMs form because of dispermy followed by loss of maternal DNA. (C) Most biparental hydatidiform moles (BiHMs) have a normal karyotype but exhibit a molar phenotype owing to imprinting defects in the maternal genome. Fertilisation occurs as normal. *Maternal genome is abnormally imprinted, e.g. owing to biallelic mutations in KHDC3L or NLRP7.

Fig. 3.

The positive DNA methyltransferase (DNMT)–miR-497-5p–SALL4 loop, as proposed by Peng et al. (2021), allows CC cells to maintain stem-like properties. In healthy cells (top), miR-497-5p is expressed from the MIR497 gene and negatively regulates SALL4 expression. In CC (bottom), it is proposed that aberrant expression of SALL4 leads to recruitment of DNMTs to the promoter of miR-497-5p, leading to its methylation, which blocks expression of the miRNA. Removal of the silencing miR-497-5p leads to increased production of the transcription factor SALL4, which allows CC cells to upregulate other pathways that are involved in invasion, migration and therapy resistance.