NLRP7 and the genetics of post-molar choriocarcinomas in Senegal.

Gestational choriocarcinomas are malignant tumors of trophoblastic cells that affect 5-25% of women with sporadic hydatidiform moles (HMs) depending on countries and studies. Nucleotide binding and oligomerization domain-like receptor protein 7 (NLRP7) is a major gene responsible for recurrent HMs and recently mutations in this gene have also been shown in 13% of women with sporadic, non-recurrent  moles. To investigate the role of NLRP7 in the genetic susceptibility for the malignant degeneration of moles, we sequenced its 11 exons in 43 Senegalese patients with post-molar choriocarcinomas. We report the presence of three novel NLRP7 variants that were found only in patients but not in 100 controls from the Senegalese general population, 100 controls from the Tunisian general population, and 100 controls from the Canadian population. In addition, this analysis revealed significant differences in the frequencies of four non-synonymous NLRP7 variants between European and Senegalese controls with the biggest difference being for variant G487E present at a minor allele frequency of 3.5% in Europeans, 18.1% in Tunisians and 45.6% in Senegalese. Comparing human NLRP7 and its paralog, NLRP2, with their mammalian counterparts revealed that allele E at position 487 is most likely the ancestral allele that was acquired in Africa but driven to low frequencies in Europeans and Asians due to migration, population bottlenecks and selective pressures. This study is the first attempt to investigate the role of NLRP7 in choriocarcinomas and highlights the higher frequencies of NLRP7 variants in the general Senegalese and Tunisian populations both known to have higher frequencies of moles and choriocarcinomas.

Differential expression of E-cadherin, ß-catenin, and Lewis x between invasive hydatidiform moles and post-molar choriocarcinomas.

Trophoblast cell adhesion and migration are carefully coordinated during normal placental development. We have compared the expression of three adhesion molecules, E-cadherin, ß-catenin, and Lewis x, by immunohistochemistry during normal trophoblast differentiation, and in hydatidiform moles and choriocarcinomas. Both E-cadherin and ß-catenin were expressed in normal placenta cytotrophoblast, and this expression decreased with trophoblast maturation. E-cadherin was mainly localized along the contact between cytotrophoblast and syncytiotrophoblast, which indicates its role in the differentiation of the syncytial layer. Lewis x disappeared progressively during differentiation of normal villous vessels, and was expressed in molar pregnancies. Interestingly, whereas choriocarcinomas were not, or poorly, stained, invasive hydatidiform moles (invHMs) strongly expressed Lewis x in vascular structures. This observation correlated well with E-cadherin and ß-catenin expression and suggests that these three markers are associated with the invasive transformation. The presence of robust endothelial structures in invHMs could also explain their ability to maintain organized villous architecture (contrary to metastatic choriocarcinomas) during their invasion of extrauterine tissues such as the lung or the brain after dissemination through the blood flow. In our hands, Lewis x appeared to be a new, reliable marker that can be used to clearly distinguish invHMs from choriocarcinomas.

Genome-wide high-resolution aCGH analysis of gestational choriocarcinomas.

Eleven samples of DNA from choriocarcinomas were studied by high resolution CGH-array 244 K. They were studied after histopathological confirmation of the diagnosis, of the androgenic etiology and after a microsatellite marker analysis confirming the absence of contamination of tumor DNA from maternal DNA. Three cell lines, BeWo, JAR, JEG were also studied by this high resolution pangenomic technique. According to aCGH analysis, the de novo choriocarcinomas exhibited simple chromosomal rearrangements or normal profiles. The cell lines showed various and complex chromosomal aberrations. 23 Minimal Critical Regions were defined that allowed us to list the genes that were potentially implicated. Among them, unusually high numbers of microRNA clusters and imprinted genes were observed.