Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes

Abstract

Hydatidiform mole (HM) is an aberrant human pregnancy characterized by excessive trophoblastic proliferation and abnormal embryonic development. HM have two morphological types, complete (CHM) and partial (PHM), and non-recurrent ones have three genotypic types, androgenetic monospermic, androgenetic dispermic, and triploid dispermic. Most available studies on risk factors predisposing to different types of HM and their malignant transformation mainly suffer from the lack of comprehensive genotypic analysis of large cohorts of molar tissues combined with accurate postmolar hCG follow-up. Moreover, 10-20% of patients with one HM have at least one non-molar miscarriage, which is higher than the frequency of two pregnancy losses in the general population (2-5%) suggesting a common genetic susceptibility to HM and miscarriages. However, the underlying causes of the miscarriages in these patients are unknown. Here, we comprehensively analyzed 204 HM, mostly from patients referred to the Quebec Registry of Trophoblastic Diseases and for which postmolar hCG monitoring are available, and 30 of their non-molar miscarriages. We revisited the risk of maternal age and neoplastic transformation across the different HM genotypic categories and investigated the presence of chromosomal abnormalities in their non-molar miscarriages. We confirm that androgenetic CHM are more prone to gestational trophoblastic neoplasia (GTN) than triploid dispermic PHM, and androgenetic dispermic CHM are more prone to high risk GTN and choriocarcinoma (CC) than androgenetic monospermic CHM. We also confirm the association between increased maternal age and androgenetic CHM and their malignancies. Most importantly, we demonstrate for the first time that patients with an HM and miscarriages are at higher risk for aneuploid miscarriages [83.3%, 95% confidence interval (CI) 0.653-0.944] than women with sporadic (51.5%, 95% CI 50.3-52.7%, p-value = 0.0003828) or recurrent miscarriages (43.8%, 95% CI 40.7-47.0%, p-value = 0.00002). Our data suggest common genetic female germline defects predisposing to HM and aneuploid non-molar miscarriages in some patients.

ABO blood type compatibility is not a risk factor for gestational trophoblastic neoplasia development from androgenetic complete hydatidiform moles

“…Thus, the results discussed above might not be conclusive. In this study population, the reported risk factors of GTN development, namely patient's age and serum hCG level, showed the same impact as previously reported (Table 2 and Table ) 3,4 . Maternal ages of the patients with AB blood type were a little high, although this was not statistically significant (Table ).…”

“…The incidences of GTN from CHMs and PHMs are 15%‐20% and 1%‐2%, respectively 1,2 . Thus, androgenetic CHMs are a major source of GTN, but the developing mechanism of GTN has not been revealed, although increased patient age and high serum human chorionic gonadotropin (hCG) level have been reported as risk factors 3,4 . Characteristically, both CHMs and GTN from CHMs are complete allografts for patients because they are derived from conceptus tissues without maternal chromosomes 1,2 .…”

Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important

“…These maternal effect variants account for up to 50% of MLID cases [10] and affect proteins of the subcortical complex of the oocyte [9] which mediates the proper imprinting in embryonic development. Women carrying maternal effect, variants are healthy, but are at a higher risk for children with disturbed imprinting without predictable phenotypes, hydatidiform moles, aneuploidies, and miscarriages [27,28]. In case maternal effect variants can be identified, an adapted reproductive management including oocyte donation should be discussed [29].…”

Parental contribution to trisomy in heterozygous androgenetic complete moles

“…The relationship between the developing potential of GTN and genetic constitutions has been discussed for several decades. The risk of developing GTN is higher for dispermic CHMs than for monospermic CHM 8,9 . Our previous study did not support this idea (monospermic CHM; 14%[29/204] vs. dispermic CHM; 21%[6/28], P = 0.40, Fisher's exact test) 6 .…”

“…We reviewed the STR electropherograms of 31 heterozygous and 236 homozygous androgenetic CHMs. Among 16 loci of PowerPlex 16 system, the medians and ranges of two allelic loci of patients' blood and CHMs in androgenetic heterozygous CHMs were 12 (8)(9)(10)(11)(12)(13)(14) and 7 (3-11), respectively (Supplementary Table S4 online). The minimum number of two allelic loci in heterozygous CHM was 3.…”