RESUMEN
Assessing fertilized human embryos is crucial for in vitro fertilization, a task being revolutionized by artificial intelligence. Existing models used for embryo quality assessment and ploidy detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we develop and compare various embryo ploidy status prediction models across distinct embryo development stages. We present BELA, a state-of-the-art ploidy prediction model that surpasses previous image- and video-based models without necessitating input from embryologists. BELA uses multitask learning to predict quality scores that are thereafter used to predict ploidy status. By achieving an area under the receiver operating characteristic curve of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists' manual scores. While not a replacement for preimplantation genetic testing for aneuploidy, BELA exemplifies how such models can streamline the embryo evaluation process.
Asunto(s)
Aneuploidia , Blastocisto , Desarrollo Embrionario , Ploidias , Imagen de Lapso de Tiempo , Humanos , Imagen de Lapso de Tiempo/métodos , Blastocisto/citología , Desarrollo Embrionario/genética , Femenino , Fertilización In Vitro , Curva ROCRESUMEN
OBJECTIVE: This study aimed to comprehensively analyze the detection capacity of non-invasive prenatal testing (NIPT) for chromosomal abnormalities of all 24 chromosomes, as well as high-risk indications for pregnancy and the fetal fraction, in a large cohort. METHODS: We retrospectively enrolled 118,969 pregnant women who underwent NIPT at Sichuan Provincial Maternity and Child Health Care Hospital from March 2019 to June 2022. The sensitivity, specificity, positive predictive value, negative predictive value, and positive chromosomal abnormality rate were calculated. The fetal fraction based on gestational age, maternal body mass index, and number was examined. RESULTS: NIPT demonstrated > 99% sensitivity and specificity for almost all of the common trisomies (T21, T18, and T13), sex chromosomal aneuploidies, rare autosomal trisomies, and microdeletion/microduplication syndromes. Positive predictive values varied from 12.0% to 89.6%. Advanced maternal age was associated with an increased risk of three major aneuploidies. The fetal fraction was positively correlated with gestational age and negatively correlated with the maternal body mass index. CONCLUSIONS: NIPT can be used to effectively screen for chromosomal abnormalities across all 24 chromosomes. Advanced maternal age is a risk factor for high-risk pregnancy, and careful consideration of the fetal fraction is essential during NIPT.
Asunto(s)
Pruebas Prenatales no Invasivas , Humanos , Femenino , Embarazo , Adulto , China/epidemiología , Pruebas Prenatales no Invasivas/métodos , Estudios Retrospectivos , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/epidemiología , Aberraciones Cromosómicas , Edad Gestacional , Edad Materna , Adulto Joven , Aneuploidia , Índice de Masa CorporalRESUMEN
High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities. Although genotyping-by-sequencing (GBS)-based haplotyping methods enabled PGT for monogenic disorders (PGT-M), structural rearrangements (PGT-SR), and aneuploidies (PGT-A), they are labour intensive, only partially cover the genome and are troublesome for difficult loci and consanguineous couples. Here, we devise a simple, scalable and universal whole genome sequencing haplarithmisis-based approach enabling all forms of PGT in a single assay. In a comparison to state-of-the-art GBS-based PGT for nuclear DNA, shallow sequencing-based PGT, and PCR-based PGT for mitochondrial DNA, our approach alleviates technical limitations by decreasing whole genome amplification artifacts by 68.4%, increasing breadth of coverage by at least 4-fold, and reducing wet-lab turn-around-time by ~2.5-fold. Importantly, this method enables trio-based PGT-A for aneuploidy origin, an approach we coin PGT-AO, detects translocation breakpoints, and nuclear and mitochondrial single nucleotide variants and indels in base-resolution.
Asunto(s)
Diagnóstico Preimplantación , Secuenciación Completa del Genoma , Humanos , Diagnóstico Preimplantación/métodos , Secuenciación Completa del Genoma/métodos , Femenino , Fertilización In Vitro/métodos , Pruebas Genéticas/métodos , Aneuploidia , Embarazo , ADN Mitocondrial/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Genoma Humano/genéticaRESUMEN
Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.
Asunto(s)
Aneuploidia , Daño del ADN , Sistema de Señalización de MAP Quinasas , Ftalazinas , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ftalazinas/farmacología , Línea Celular Tumoral , Piperazinas/farmacología , Quinasas raf/metabolismo , Quinasas raf/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Sistemas CRISPR-Cas , Línea Celular , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Resistencia a Antineoplásicos/genéticaRESUMEN
BACKGROUND: Whole exome sequencing (WES) has been recommended to investigate the genetic cause of fetal structural anomalies. In this retrospective study, we aimed to evaluate the diagnostic yield of WES in our cohort of families with pregnancy loss or termination of pregnancy due to structural anomalies. METHODS: As aneuploidy, triploidy and copy number variations (CNVs) could be detected by exome-based CNV analysis, only WES is performed in this study. And the results of 375 cases assessed by WES were analyzed. RESULTS: The overall detection rate was 32.3% (121/375), including aneuploidy and triploidy (7.5%, 28/375), CNVs (5.1%, 19/375) and single-nucleotide variants (SNVs) /insertions or deletions (Indels) (19.7%, 74/375). Among these, the diagnostic yield for likely pathogenic (LP) or pathogenic (P) CNVs is 4.8% (18/375), and the diagnostic yield for LP or P SNVs/Indels is 15.2% (57/375). And an additional 4.8% (18/375) of cases had CNVs or SNVs/Indels classified as variants of uncertain significance (VUS) with potential clinical significance. CONCLUSIONS: Our findings expand the known mutation spectrum of genetic variants related to fetal abnormalities, increase our understanding of prenatal phenotypes, and enable more accurate counseling of recurrence risk for future pregnancies.
Asunto(s)
Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Humanos , Femenino , Secuenciación del Exoma/métodos , Embarazo , Variaciones en el Número de Copia de ADN/genética , Estudios Retrospectivos , Adulto , Feto , Pruebas Genéticas/métodos , Aborto Espontáneo/genética , AneuploidiaRESUMEN
Genetic counseling of mosaic and non-mosaic tetrasomy 9p remains difficult because of the possible associated congenital abnormalities, cytogenetic discrepancy in various tissues, true-positive and false-positive diagnosis in non-invasive prenatal testing (NIPT), uniparental disomy (UPD) 9, tissue-limited mosaicism, perinatal progressive decrease of the aneuploid cell line, phenotypic normal carriers and possible favorable fetal outcome in the cases with mosaic tetrasomy 9p at amniocentesis. This article presents a comprehensive review of various counseling issues concerning mosaic and non-mosaic tetrasomy 9p at prenatal diagnosis, and the information provided is very useful for genetic counseling under such circumstances.
Asunto(s)
Amniocentesis , Aneuploidia , Cromosomas Humanos Par 9 , Asesoramiento Genético , Mosaicismo , Humanos , Mosaicismo/embriología , Embarazo , Femenino , Cromosomas Humanos Par 9/genética , Diagnóstico Prenatal/métodos , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/embriología , Trastornos de los Cromosomas/genética , Pruebas Prenatales no Invasivas/métodosRESUMEN
OBJECTIVE: We present mosaic distal 13q duplication due to mosaic unbalanced translocation 46,XY,der(14)t(13;14)(q32.2;p13)/46,XY at amniocentesis in a pregnancy associated with a favorable fetal outcome. CASE REPORT: A 37-year-old, gravida 2, para 0, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY, add(14) (p13)[17]/46,XY[13] (56.6% mosaicism). Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed arr 13q32.2q34 × 2â¼3, consistent with 45% mosaicism for distal 13q duplication. Repeat amniocentesis at 24 weeks of gestation revealed a karyotype of 46,XY,der(14)t(13;14)(q32.2;p13)[14]/46,XY[16] (46.6% mosaicism). The parental karyotypes were normal. aCGH analysis on the DNA extracted from uncultured amniocytes revealed arr 13q32.2q34 × 2.38, consistent with 30-40% mosaicism for distal 13q duplication. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes detected 22.8% (23/101 cells) mosaicism for distal 13q duplication. Prenatal ultrasound findings were unremarkable. At 39 weeks of gestation, a 3616-g phenotypically normal baby was delivered. The karyotypes of cord blood, umbilical cord and placenta were 46,XY,der(14)t(13;14)(q32.2;p13)[20]/46,XY[20] (50% mosaicism), 46,XY,der(14)t(13;14)(q32.2;p13)[14]/46,XY[26] (35% mosaicism) and 46,XY (40/40 cells) (0% mosaicism), respectively. When follow-ups at the age of 4½ months and the age of one year, the peripheral blood had the karyotype of 46,XY,der(14)t(13;14)(q32.2;p13)[18]/46,XY[22] (45% mosaicism). Interphase FISH analysis on buccal mucosal cells at the age of 4½ months revealed 2.7% (3/110 cells) mosaicism for distal 13q duplication, compared with 1% (1/100 cells) in the normal control. The neonate was normal in phenotype and development. CONCLUSIONS: Mosaic unbalanced translocation at amniocentesis can be associated with a favorable fetal outcome, perinatal progressive decrease of the aneuploid cell line and cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes.
Asunto(s)
Amniocentesis , Cromosomas Humanos Par 13 , Mosaicismo , Translocación Genética , Humanos , Femenino , Embarazo , Mosaicismo/embriología , Adulto , Translocación Genética/genética , Cromosomas Humanos Par 13/genética , Hibridación Genómica Comparativa , Cromosomas Humanos Par 14/genética , Cariotipificación , Aneuploidia , Trisomía/genética , Cariotipo , Resultado del Embarazo/genética , Duplicación Cromosómica/genética , Hibridación Fluorescente in SituAsunto(s)
Cromosomas Humanos Par 9 , Segundo Trimestre del Embarazo , Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Ultrasonografía Prenatal/métodos , Cromosomas Humanos Par 9/genética , Adulto , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Análisis por Micromatrices/métodos , Reacción en Cadena de la Polimerasa/métodos , Aneuploidia , Aberraciones Cromosómicas/embriologíaRESUMEN
Placental diseases may affect the outcome of pregnancy and long-term health of the mother and fetus. Fetal fraction is a key indicator for the success of non-invasive prenatal testing, and has been associated with gestational age, body mass index and fetal chromosomal aneuploidies. Many studies have found that fetal fraction is also related to placenta-derived diseases and may become a new predictor for such diseases. This article has summarized the association between the two, with an aim to provide new ideas for the prediction of placental diseases.
Asunto(s)
Enfermedades Placentarias , Diagnóstico Prenatal , Humanos , Embarazo , Femenino , Enfermedades Placentarias/genética , Enfermedades Placentarias/diagnóstico , Diagnóstico Prenatal/métodos , Feto , Aneuploidia , Placenta/metabolismo , Edad GestacionalRESUMEN
The sclerotia of Wolfiporia hoelen are one of the most important traditional Chinese medicines and foods commonly used in China, Japan, Korea, and other Asian countries. To provide a high-quality reference genome and deepen our understanding of the genome of W. hoelen to elucidate various biological phenomena. In this study, we assembled three genomes of W. hoelen using a combination of Nanopore and Illumina sequencing strategies. The fifteen-chromosome genome L7 of W. hoelen was assembled with two-sided telomere and rDNA sequences for the first time. The chromosome count was subsequently confirmed through collinearity analysis, correcting the previous belief that W. hoelen had only fourteen chromosomes. Moreover, the aneuploid genome was discovered in W. hoelen for the first time through sequencing depth analysis of different chromosomes, and only some strains of W. hoelen exhibit aneuploid genomes. According to the genome analysis of homokaryotic offspring and protoplast-isolated strains, a potential variation in chromosome allocation patterns was revealed. Moreover, the gene function enrichment analysis of genes on reduplicated chromosomes demonstrated that aneuploidy in the genome may be the result of environmental adaptation for W. hoelen. The discovery of an aneuploid genome also provides new ideas for genetic improvement of W. hoelen.
Asunto(s)
Aneuploidia , Cromosomas Fúngicos/genética , Genoma Fúngico , Medicina Tradicional China , Hypocreales/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Adaptación Fisiológica/genéticaRESUMEN
Cytogenetic information about the product of conception (POC) is important to determine the presence of recurrent chromosomal abnormalities that are an indication for preimplantation genetic testing for aneuploidy or structural rearrangements. Although microscopic examination by G-staining has long been used for such an evaluation, detection failures are relatively common with this method, due to cell-culture-related issues. The utility of low-coverage whole-genome sequencing (lcWGS) using short-read next-generation sequencing (NGS) has been highlighted recently as an alternative cytogenomic approach for POC analysis. We, here, performed comparative analysis of two NGS-based protocols for this purpose based on different short-read sequencers (the Illumina VeriSeq system using a MiSeq sequencer and the Thermo Fisher ReproSeq system using an Ion S5 sequencer). The cytogenomic diagnosis obtained with each NGS method was equivalent in each of 20 POC samples analyzed. Notably, X chromosome sequence reads were reduced in some female samples with both systems. The possibility of low-level mosaicism for monosomy X as an explanation for this was excluded by FISH analysis. Additional data from samples with various degrees of X chromosome aneuploidy suggested that it was a technical artifact related to X chromosome inactivation. Indeed, subsequent nanopore sequencing indicated that the DNA in the samples showing the artifact was predominantly unmethylated. Our current findings indicate that although X chromosome data must be interpreted with caution, both the systems we tested for NGS-based lcWGS are useful alternatives for the karyotyping of POC samples.
Asunto(s)
Aneuploidia , Secuenciación de Nucleótidos de Alto Rendimiento , Cariotipificación , Humanos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Cariotipificación/métodos , Cromosomas Humanos X/genética , Diagnóstico Preimplantación/métodos , Secuenciación Completa del Genoma/métodos , Embarazo , MasculinoRESUMEN
Polyploids are essential in plant evolution and species formation, providing a rich genetic reservoir and increasing species diversity. Complex polyploids with higher ploidy levels often have a dosage effect on the phenotype, which can be highly detrimental to gametes, making them rare. In this study, offspring plants resulting from an autoallotetraploid (RRRC) derived from the interspecific hybridization between allotetraploid Raphanobrassica (RRCC, 2n = 36) and diploid radish (RR, 2n = 18) were obtained. Fluorescence in situ hybridization (FISH) using C-genome-specific repeats as probes revealed two main genome configurations in these offspring plants: RRRCC (2n = 43, 44, 45) and RRRRCC (2n = 54, 55), showing more complex genome configurations and higher ploidy levels compared to the parental plants. These offspring plants exhibited extensive variation in phenotypic characteristics, including leaf type and flower type and color, as well as seed and pollen fertility. Analysis of chromosome behavior showed that homoeologous chromosome pairing events are widely observed at the diakinesis stage in the pollen mother cells (PMCs) of these allopolyploids, with a range of 58.73% to 78.33%. Moreover, the unreduced C subgenome at meiosis anaphase II in PMCs was observed, which provides compelling evidence for the formation of complex allopolyploid offspring. These complex allopolyploids serve as valuable genetic resources for further analysis and contribute to our understanding of the mechanisms underlying the formation of complex allopolyploids.
Asunto(s)
Aneuploidia , Cromosomas de las Plantas , Poliploidía , Raphanus , Raphanus/genética , Cromosomas de las Plantas/genética , Hibridación Fluorescente in Situ , Brassica/genética , Hibridación Genética , Meiosis/genética , Genoma de Planta , Polen/genética , FenotipoRESUMEN
PURPOSE: To determine the factors influencing the likelihood of biochemical pregnancy loss (BPL) after transfer of a euploid embryo from preimplantation genetic testing for aneuploidy (PGT-A) cycles. METHODS: The study employed an observational, retrospective cohort design, encompassing 6020 embryos from 2879 PGT-A cycles conducted between February 2013 and September 2021. Trophectoderm biopsies in day 5 (D5) or day 6 (D6) blastocysts were analyzed by next generation sequencing (NGS). Only single embryo transfers (SET) were considered, totaling 1161 transfers. Of these, 49.9% resulted in positive pregnancy tests, with 18.3% experiencing BPL. To establish a predictive model for BPL, both classical statistical methods and five different supervised classification machine learning algorithms were used. A total of forty-seven factors were incorporated as predictor variables in the machine learning models. RESULTS: Throughout the optimization process for each model, various performance metrics were computed. Random Forest model emerged as the best model, boasting the highest area under the ROC curve (AUC) value of 0.913, alongside an accuracy of 0.830, positive predictive value of 0.857, and negative predictive value of 0.807. For the selected model, SHAP (SHapley Additive exPlanations) values were determined for each of the variables to establish which had the best predictive ability. Notably, variables pertaining to embryo biopsy demonstrated the greatest predictive capacity, followed by factors associated with ovarian stimulation (COS), maternal age, and paternal age. CONCLUSIONS: The Random Forest model had a higher predictive power for identifying BPL occurrences in PGT-A cycles. Specifically, variables associated with the embryo biopsy procedure (biopsy day, number of biopsied embryos, and number of biopsied cells) and ovarian stimulation (number of oocytes retrieved and duration of stimulation), exhibited the strongest predictive power.
Asunto(s)
Aborto Espontáneo , Aneuploidia , Pruebas Genéticas , Aprendizaje Automático , Diagnóstico Preimplantación , Humanos , Femenino , Embarazo , Diagnóstico Preimplantación/métodos , Estudios Retrospectivos , Adulto , Pruebas Genéticas/métodos , Aborto Espontáneo/diagnóstico , Aborto Espontáneo/genética , Aborto Espontáneo/epidemiología , Transferencia de Embrión/métodos , BlastocistoRESUMEN
BACKGROUND: Non-invasive chromosome screening (NICS) and trophectoderm biopsy preimplantation genetic testing for aneuploidy (TE-PGT) were both applied for embryo ploidy detection, However, the cumulative live birth rates (CLBR) of NICS and TE-PGT in older age groups have yet to be reported. This study aimed to ascertain whether NICS and TE-PGT could enhance the cumulative live birth rates among patients of advanced maternal age. METHODS: A total of 384 couples aged 35-40 years were recruited. The patients were assigned to three groups: NICS, TE-PGT, and intracytoplasmic sperm injection (ICSI). All patients received frozen single blastocyst transfer. Patients in the NICS and TE-PGT groups underwent aneuploidy screening. RESULTS: When compared to the ICSI group, the CLBR was significantly higher in the NICS and TE-PGT groups (27.9% vs. 44.9% vs. 51.0%, p = 0.003 for NICS vs. ICSI, p < 0.001 for TE-PGT vs. ICSI). There were no significant differences in the clinical outcomes between the NICS and TE-PGT groups. Adjusting for confounding factors, the NICS and TE-PGT groups still showed a higher CLBR than the ICSI group (adjusted odds ratio (OR) 3.847, 95% confidence interval (CI) 1.939 to 7.634; adjusted OR 3.795, 95% CI 1.981 to 7.270). Additionally, the cumulative pregnancy loss rates of the NICS and TE-PGT groups were significantly lower than that of the ICSI group (adjusted OR 0.277, 95% CI 0.087 to 0.885; adjusted OR 0.182, 95% CI 0.048 to 0.693). There was no significant difference in the birth weights of the three groups (p = 0.108). CONCLUSIONS: In women 35-40 years old, the CLBR can be increased by selecting euploid embryos using NICS and TE-PGT. For elderly women at high risk of embryonic aneuploidy, NICS, characterized by its safety and non-invasive nature, may emerge as an alternative option for preimplantation genetic testing.
Asunto(s)
Aneuploidia , Pruebas Genéticas , Edad Materna , Diagnóstico Preimplantación , Inyecciones de Esperma Intracitoplasmáticas , Humanos , Femenino , Diagnóstico Preimplantación/métodos , Adulto , Embarazo , Estudios Prospectivos , Pruebas Genéticas/métodos , Nacimiento Vivo , Tasa de Natalidad , Índice de Embarazo , Masculino , Transferencia de Embrión/métodosRESUMEN
Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose-response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies.
Asunto(s)
Aneuploidia , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Femenino , Biomarcadores de Tumor/genética , Masculino , Mutación , Persona de Mediana Edad , Anciano , Inmunoterapia/métodos , Telomerasa/genéticaRESUMEN
Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21, with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.
Asunto(s)
Aneuploidia , Carcinogénesis , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Progresión de la Enfermedad , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Carcinogénesis/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Cromosomas Humanos Par 8/genética , Regulación Neoplásica de la Expresión Génica , Daño del ADNRESUMEN
The discovery of DNA in blastocoel fluid (BF-DNA) generated new perspectives in the potential development of simpler and safer alternative non-invasive tests in reproductive genetics. Short DNA fragments of apoptotic origin, together with specific expression patterns of pro- and anti-apoptotic genes in the blastocoel fluid of euploid and aneuploid embryos, suggest a self-correction mechanism to preferentially eliminate aneuploid cells, and purge defective and non-viable cells. The correlation of blastocoel fluid content with the genetic status of the whole embryo, and therefore its potential use in minimally invasive preimplantation genetic testing (miPGT), or as an indicator of embryo potential, remains uncertain and needs to be determined. The limited amount and compromised integrity of BF-DNA, with likely apoptotic origination, constrains its amplification, leading to low concordance and reproducibility rates for both aneuploidy screening and monogenic testing. While embryo genotyping constitutes a more ambitious goal, the presence of analysable DNA after amplification in blastocoel fluid may be used as a clinical biomarker of embryo competency to select the most viable embryo(s) for transfer, and potentially improve the implantation rate. Although blastocentesis remains a promising area for future research, several technical and methodological limitations are currently constraining its consideration for clinical practice.