A case of intraplacental gestational choriocarcinoma; characterised by the methylation pattern of the early placenta and an absence of driver mutations

Abstract

Background Gestational choriocarcinoma is a rare malignancy believed to arise from the trophoblast cells of the placenta. Despite the frequently aggressive clinical nature, choriocarcinoma has been routinely curable with cytotoxic chemotherapy for over 50 years. To date little is known regarding the route to oncogenesis in this malignancy. Methods In a case of intraplacental choriocarcinoma, we have performed detailed genetic studies including microsatellite analysis, whole genome sequencing (WGS) and methylation analysis of the tumour and surrounding mature placenta. Results The results of the WGS sequencing indicated a very low level of mutation and the absence of any driver mutations or oncogene activity in the tumour. The methylation analysis identified a distinctly different profile in the tumour from that of the mature placenta. Comparison with a panel of reference methylation profiles from different stages of placental development indicated that the tumour segregated with the first trimester samples. Conclusions These findings suggest that gestational choriocarcinoma is likely to arise as a result of aberrations of methylation during development, rather than from DNA mutations. The results support the hypothesis that gestational choriocarcinoma arises from a normally transient early trophoblast cell. At this point in development this cell naturally has a phenotype of rapid division, tissue invasion and sensitivity to DNA damaging chemotherapy that is very similar to that of the mature choriocarcinoma cell. Electronic supplementary material The online version of this article (10.1186/s12885-019-5906-8) contains supplementary material, which is available to authorized users.

Genetics of gestational trophoblastic disease

“…The relatively high risk of requiring chemotherapy following a CHM and lesser, but still increased, risk after a PHM suggests aberrant genomic imprinting is likely to play a role in the development of post-mole tumours. Recent analysis of DNA from an intraplacental choriocarcinoma, revealed a very different methylation profile for the tumour and the surrounding normal term placenta, suggesting that epigenetic changes, rather than an accumulation of mutations, may also have a role in the development of tumours following non-molar pregnancies [75].…”

An Overview of the Role of Long Non-Coding RNAs in Human Choriocarcinoma

“…To date, little is known regarding the underlying pathophysiology and oncogenesis in this malignancy. Gestational CC is likely to arise as a result of aberrations of methylation during development, rather than from DNA mutations, supporting the hypothesis that it arises from normally transient early trophoblast cells [ 10 ]. At a molecular level, gestational CC is also characterized by an overexpression of TP53 , MDM2 , and epidermal growth factor receptor ( EGFR ), and downregulation of a number of genes, including NECC1 , DOC-2/hDab2 , KRAS , CDH1 , CDKN2A , HIC-1, and TIMP3 [ 8 ].…”

Demographics, natural history and treatment outcomes of non‐molar gestational choriocarcinoma: a UK population study

“…However, recent observations that choriocarcinoma may be linked to aberrations in the progression of methylation and the observation than healthy fetal cells remain in the maternal circulation for years after pregnancy, suggest that mechanisms may be very different from other malignancies. 25,26 Previous data have indicated the close relation between the FIGO prognostic score and treatment outcomes. 9,27,28 The present study supports those earlier reports, with the 81 patients falling into the low-risk group having a 100% cure rate, the 107 patients in the high-risk group a 96% cure rate and the 46 patients in the ultra-high-risk group an 80.5% cure rate.…”

“…The processes behind the development of the malignant phenotype in gestational choriocarcinoma and the mechanisms underlying the potentially long period of quiescent cell survival are at present uncertain. However, recent observations that choriocarcinoma may be linked to aberrations in the progression of methylation and the observation than healthy fetal cells remain in the maternal circulation for years after pregnancy, suggest that mechanisms may be very different from other malignancies 25,26…”