RESUMO
Hydatidiform moles are abnormal conceptuses. Many hydatidiform moles are diploid androgenetic, and of these, most are homozygous in all loci. Additionally, most hydatidiform moles are euploid. Using Single Nucleotide Polymorphism (SNP) array analysis, in two studies a higher frequency of aneuploidy was observed in diploid androgenetic heterozygous conceptuses, than in their homozygous counterparts. In the Danish Mole Project, we analyze conceptuses suspected to be hydatidiform moles due to the clinical presentation, using karyotyping and Short Tandem Repeat (STR) analysis. Among 278 diploid androgenetic conceptuses, 226 were homozygous in all loci and 52 (18.7%) were heterozygous in several loci. Among 142 triploid diandric conceptuses, 141 were heterozygous for paternally inherited alleles in several loci. Here we show that the frequencies of aneuploidy in diploid androgenetic heterozygous and triploid diandric heterozygous conceptuses were significantly higher than the frequency of aneuploidy in diploid androgenetic homozygous conceptuses. In diploid androgenetic and triploid diandric conceptuses that are heterozygous for paternally inherited alleles, the two paternally inherited sets of genomes originate in two spermatozoa. Each spermatozoon provides one pair of centrioles to the zygote. The presence of two pairs of centrioles may cause an increased risk of aneuploidy.
Assuntos
Mola Hidatiforme , Neoplasias Uterinas , Masculino , Gravidez , Feminino , Humanos , Diploide , Triploidia , Mola Hidatiforme/genética , Heterozigoto , AneuploidiaRESUMO
AIMS: Radio(chemo)therapy plays an important role in the treatment of vulvar cancer, either as postoperative treatment or as definitive treatment in patients who present with inoperable disease. Only limited data are available regarding outcome after modern state of the art radio(chemo)therapy and more information regarding prognostic factors are warranted. The aim of this study was to evaluate disease outcomes after radio(chemo)therapy in patients with vulvar cancer with special emphasis on the impact of lichen sclerosis on local control. MATERIALS AND METHODS: All consecutive patients (n = 109) from the western half of Denmark who were treated with definitive (n = 52) or postoperative (n = 57) radio(chemo)therapy between January 2013 and January 2020 were included. Local control, cause-specific survival and overall survival, as well as morbidity, were analysed using Kaplan-Meier statistics. Prognostic factors for local control were analysed in univariate and multivariate analysis. RESULTS: At a median follow-up of 35 (4-95) months, 46 (42.0%) patients were diagnosed with recurrence. Eighty per cent of the recurrences were located to the vulva region, leading to a 5-year local control of 58.9% (confidence interval 47.9-69.9). Cause-specific survival was 62.9% (confidence interval 53.1-72.7), whereas overall survival was 58.0% (confidence interval 47.6-68.5). Grade 3-4 morbidity was diagnosed in 10 (9%) patients. Lichen sclerosis (hazard ratio 3.89; confidence interval 1.93-7.79) was an independent risk factors for local recurrence. Patients without lichen sclerosis had a 5-year local control rate of 83.6% (confidence interval 67.2-99.0) and 62.6% (confidence interval 43.2-82.0) after postoperative and definitive radio(chemo)therapy, respectively. In patients with lichen sclerosis, the local control rate was 44.0% (confidence interval 19.3-69.0) and 17.6% (confidence interval 0-30.0) after postoperative and definitive radio(chemo)therapy, respectively. CONCLUSION: Radio(chemo)therapy plays an important role in the treatment of vulvar cancer. However, despite dose escalation, a substantial proportion of patients experienced local relapse. Pre-existing lichen sclerosis seems to have a significant impact on the risk of recurrence. This should influence surveillance programmes for these patients.
Assuntos
Líquen Escleroso e Atrófico , Neoplasias Vulvares , Feminino , Humanos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologiaRESUMO
Women with mutation in both alleles of the NLRP7 or C6orf221/KHDC3L genes are predisposed to diploid biparental moles, but it has also been suggested that mutation in these genes can predispose to diploid androgenetic or triploid moles and to other kinds of reproductive wastage. We have investigated the association between molar pregnancy and recurrent miscarriages regarding changes in the NLRP7 and C6orf221/KHDC3L genes. Our study group can be divided into three sub-cohorts: (i) women having had at least one molar pregnancy and at least two non-mole miscarriages, (ii) women having had recurrent androgenetic hydatidiform moles and (iii) women having had one diploid androgenetic hydatidiform mole and a relative having had a hydatidiform mole (familial hydatidiform moles). We observed a statistically non-significant tendency of non-synonymous variants in NLRP7 to be more frequent in women with familial hydatidiform mole and in women with female family members with hydatidiform mole or non-mole miscarriage compared with women with no family history of mole or miscarriage. However, we did not find any unequivocal pathogenic mutations (the term 'unequivocal pathogenic mutations' refers to mutations that indubitably have a pathogenic effect on the affected woman) in NLRP7 or C6orf221/KHDC3L in any of the women in the study group. This indicates that recurrent miscarriages plus hydatidiform mole, recurrent androgenetic hydatidiform moles and familial androgenetic hydatidiform moles in general do not have the same monogenetic etiology as familiar diploid biparental moles.
Assuntos
Aborto Habitual/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Mola Hidatiforme/genética , Proteínas/genética , Aborto Habitual/epidemiologia , Estudos de Coortes , Análise Mutacional de DNA , Dinamarca/epidemiologia , Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Mola Hidatiforme/epidemiologia , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
OBJECTIVE: When a triploid pregnancy is diagnosed prenatally, gynaecologists have traditionally relied on the histopathological examination of the tissue from the terminated pregnancy to determine if the pregnancy is molar. However, reproducibility is poor and variability is high when diagnosing hydatidiform moles. Triploid pregnancies can have either the chromosomal constitution of two maternal and one paternal set, or two paternal and one maternal set, but only the conceptuses with two paternal sets have the potential to cause maternal complications. Therefore, it would be beneficial to introduce a method that gives the gynaecologist the parental origin of the genome of the triploid conceptus as early as possible, without delaying the process by first collecting parental samples. METHODS: Using methylation-specific multiplex ligation-dependent probe amplification, we measured methylation levels at different imprinted sites. RESULTS: We were able to correctly determine the parental origin of the genome in all 105 triploid pregnancies analysed. CONCLUSIONS: We present methylation-specific multiplex ligation-dependent probe amplification as a method capable of determining the parental origin of the genome of triploid conceptuses within 24 h; it is inexpensive, simple and easy to use, and parental samples are not needed.
Assuntos
Metilação de DNA/genética , Mola Hidatiforme/genética , Reação em Cadeia da Polimerase Multiplex , Pais , Diagnóstico Pré-Natal/métodos , Triploidia , Feminino , Humanos , Mola Hidatiforme/diagnóstico , Cariotipagem , Masculino , Gravidez , Complicações na Gravidez/genética , Reprodutibilidade dos Testes , Fatores de Risco , Neoplasias Uterinas/genéticaRESUMO
Hydatidiform moles (HMs) most often occur sporadically and are either diploid androgenetic or triploid. The very rare familial recurrent HMs (FRHMs) have been related to NLRP7 and C6orf221 mutations in the mother. FRHMs are most often diploid with both maternal and paternal origin of the molar genome. We have screened a cohort of 11 women with diploid HMs with biparental contributions to the molar genome with regard to mutations in NLRP7, NLRP2, the NLRP gene most homologous to NLRP7, and C6orf221. This was done in order to reveal if mutations in the mentioned genes play a major role in development of non-recurrent biparental moles. Recently, we have shown that eight of these diploid moles consist of two different cell lines. Only one woman had a mutation in the coding DNA sequence of NLRP7, which most likely contributed to HM development. This woman had non-mosaic repeated moles, and she was the only woman in our cohort with FRHM. We found no unequivocal pathogenic mutations in NLRP2 or C6orf221. Our observations suggest that although NLRP7 and C6orf221 mutations are related to diploid biparental FRHMs, neither of these genes, nor NLRP2, are related to diploid HMs with biparental contributions to the molar genome, in general.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mola Hidatiforme/etiologia , Mola Hidatiforme/genética , Proteínas/genética , Proteínas Reguladoras de Apoptose , Diploide , Feminino , Humanos , Mutação , GravidezRESUMO
To identify possible weaknesses in cervical screening in Aarhus County, 10 years after the programme was introduced, screening histories were examined. A major problem for the screening programme was that 31% of women were never screened and 61% under-screened, the latter group being significantly dominated by older women and high-stage tumours.
Assuntos
Programas de Rastreamento , Neoplasias do Colo do Útero/epidemiologia , Esfregaço Vaginal , Adulto , Dinamarca , Feminino , Humanos , Anamnese , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To describe and compare the current clinical features of diploid and triploid molar pregnancy and to evaluate whether the presenting clinical features can predict the ploidy of a molar pregnancy. DESIGN: A retrospective study of the clinical features and ploidy of hydatidiform moles. SETTING: The Departments of Clinical Genetics and Pathology, Aarhus University Hospital and 13 gynaecological wards, Jutland, Denmark. POPULATION: A total of 259 women with molar pregnancy diagnosed between April 1986 and June 2003. METHODS: A review of medical records of consecutively collected, clinically suspected cases of molar pregnancy was performed. The molar ploidy was determined by karyotyping, flow cytometry, and/or analysis of polymorphic DNA markers. MAIN OUTCOME MEASURES: Maternal characteristics, presenting symptoms, initial human chorionic gonadotrophin (hCG), and molar ploidy. RESULTS: In a multiple logistic regression model, initial hCG of > or = 100,000 iu/l (P < 0.001), first-trimester gestational age (P < 0.001), vaginal bleeding (P < 0.001), and maternal age of > or = 40 years (P = 0.03) were independent predictors of diploid mole. Women with excessive uterine size more frequently had a diploid than a triploid mole (P < 0.001). Fifty-four percent of the women with triploid mole and 27% of the women with diploid mole were diagnosed before onset of symptoms (P < 0.001). CONCLUSIONS: The current clinical features of diploid mole are different from those of triploid mole. The presenting clinical profile of a molar pregnancy may be used as an early predictor of the molar ploidy and thus of the prognosis.