Poaty Henriette, Coullin Philippe, Leguern Eric, Dessen Philippe, Valent Alexandre, Afoutou José-Marie, Peko Jean-Félix, Candelier Jean-Jacques, Gombé-Mbalawa Charles, Picard Jean-Yves, Bernheim Alain
Institut Gustave-Roussy, Inserm U985, Villejuif, France, Inserm, Clamart, France.
Bull Cancer. 2012 Sep;99(9):827-43. doi: 10.1684/bdc.2012.1621.
The complete hydatidiform mole (CHM), a gestational trophoblastic disease, is usually caused by the development of an androgenic egg whose genome is exclusively paternal. Due to parental imprinting, only trophoblasts develop in the absence of a fetus. CHM are diploid and no abnormal karyotype is observed. It is 46,XX in most cases and less frequently 46,XY. The major complication of this disease is gestational choriocarcinoma, a metastasizing tumor and a true allografted malignancy. This complication is infrequent in developed countries, but is more common in the developing countries and is then worsened by delayed care. The malignancies are often accompanied by acquired, possibly etiological genomic abnormalities. We investigated the presence of recurrent cytogenetic abnormalities in CHM and post-molar choriocarcinoma using metaphasic CGH (mCGH) and high-resolution 244K aCGH techniques. The 10 CHM studied by mCGH showed no chromosomal gains or losses. For post-molar choriocarcinoma, 11 tumors, whose diagnosis was verified by histopathology, were investigated by aCGH. Their androgenic nature and the absence of tumor DNA contamination by maternal DNA were verified by the analysis of microsatellite markers. Three choriocarcinoma cell lines (BeWo, JAR and JEG) were also analyzed by aCGH. The results allowed us to observe some chromosomal rearrangements in primary tumors, and more in the cell lines. Chromosomal abnormalities were confirmed by FISH and functional effect by immunohistochemical analysis of gene expression. Forty minimum critical regions (MCR) were defined on chromosomes. Candidate genes implicated in choriocarcinoma oncogenesis were selected. The presence in the MCR of many miRNA clusters whose expression is modulated by parental imprinting has been observed, for example in 14q32 or in 19q13.4. This suggests that, in gestational choriocarcinoma, the consequences of gene abnormalities directly linked to acquired chromosomal abnormalities are superimposed upon those of imprinted genes altered at fertilization.
完全性葡萄胎（CHM）是一种妊娠滋养细胞疾病，通常由一个基因组完全来自父方的雄激素化卵子发育而来。由于亲本印记，在没有胎儿的情况下仅滋养层细胞发育。CHM是二倍体，未观察到异常核型。大多数情况下为46,XX，较少见为46,XY。该疾病的主要并发症是妊娠绒毛膜癌，这是一种转移性肿瘤，也是一种真正的同种异体移植恶性肿瘤。这种并发症在发达国家并不常见，但在发展中国家更为常见，且会因治疗延迟而恶化。这些恶性肿瘤常伴有获得性的、可能是病因性的基因组异常。我们使用中期比较基因组杂交（mCGH）和高分辨率244K 全基因组芯片比较基因组杂交（aCGH）技术，研究了CHM及葡萄胎后绒毛膜癌中复发性细胞遗传学异常的存在情况。通过mCGH研究的10例CHM未显示染色体的增减。对于葡萄胎后绒毛膜癌，通过aCGH研究了11例经组织病理学确诊的肿瘤。通过微卫星标记分析验证了它们的雄激素性质以及不存在母体DNA对肿瘤DNA的污染。还通过aCGH分析了三种绒毛膜癌细胞系（BeWo、JAR和JEG）。结果使我们观察到原发性肿瘤中存在一些染色体重排，细胞系中更多。通过荧光原位杂交（FISH）证实了染色体异常，并通过基因表达的免疫组化分析证实了功能效应。在染色体上定义了40个最小关键区域（MCR）。选择了与绒毛膜癌发生相关的候选基因。例如在14q32或19q13.4中，观察到许多miRNA簇存在于MCR中，其表达受亲本印记调节。这表明，在妊娠绒毛膜癌中，与获得性染色体重排直接相关的基因异常的后果叠加在受精时改变的印记基因的后果之上。
