We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in > 10% of the individuals that we examined. Half of ...these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The ...frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define.
We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7.
Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base.
This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.
Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. ...Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile--polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.
ABSTRACT
Affecting up to 10% to 15% of all clinically recognized pregnancies, pregnancy loss has many causes. Half of first-trimester losses come about due to chromosomal abnormalities and then ...decline in frequency through pregnancy, ultimately reaching a rate of 5% in stillbirths. Recurrent pregnancy loss occurs in 1% to 2% of couples, and identifying the genetic etiology of these losses can provide psychological benefits, eliminate other testing needs, and establish a risk of recurrence. As benefits of performing genetic testing on products of conception (POCs) are clear, various groups have published practice guidelines (American College of Obstetricians and Gynecologists, European Society of Human Reproduction and Embryology, American Society for Reproductive Medicine, and Royal College of Obstetricians and Gynaecologists). However, despite the consensus for the utility of testing on POCs, requirements for these tests vary. Most appropriate testing methodology, obstetric history, and gestational age are all variations that affect the benefit or utility of these tests. As there is a lack of consensus on how to use chromosomal microarray analysis (CMA) in assessment of POCs, this study assessed POC CMA data with available karyotype data and determined the positive CMA rate for POCs. The authors also included within this data set a comprehensive correlation of CMA correlations with pregnancy phenotype, gestational age, and prior prenatal screening results. Finally, the study also assessed the impact CMA results from early losses may have on clinical care.
This cohort included 323 POC samples processed by the Brigham and Women's Hospital Center for Advanced Molecular Diagnostics in the Clinical Cytogenetics Laboratory over a consecutive 42-month period. Collected variables included estimated gestational age at time of pregnancy loss, maternal age, pregnancy phenotype results of any orthogonal testing on POC tissue, noninvasive prenatal screen results, CMA findings, and available parental karyotypes. All cases recorded gestational age except 1 sample lacking documentation. Categories of phenotypic data included lymphatic malformations, anatomical abnormalities of the fetus or placenta, twin or higher-level multiple gestations, environmental complications, amniotic fluid disorders, or the combined influence of any of the above. A lack of definitive phenotypic data excluded 3 cases from the analysis. Analyses of CMA results were categorized as normal, abnormal, or variants of uncertain significance (VUSs). The cases defined as normal had no identifiable clinically significant copy number variants, and abnormal cases were defined as pathogenic.
Results of the study included gestational age for 322 of 323 cases, which was then used to determine the rate of fetal demise or miscarriage at different gestational ages in the cohort, with first-trimester losses at <14 weeks (n = 230) and later losses defined as occurring at >14 weeks gestational age (n = 92).
The results demonstrated that frequency and genetic abnormality types (as identified by CMA) align closely with karyotype studies previously published. This means that an approximate half of the first-trimester loss cohort have a genetic abnormality, with trisomies as the most common finding. Very early losses tend to have a high positive rate of abnormalities (45.6%), which further supported CMA use in first-trimester losses. Inadvertent assessment and reporting of maternal metaphases were reduced, and yield of results improved with the implementation of CMA. Abnormal POC results may suggest balanced parental abnormalities, and follow-up parental testing in such cases is recommended. A need for additional studies exists to determine the parental follow-up studies yield.
In conclusion, POC tissue genetic testing following pregnancy loss can aid in clinical management via identification of genetic etiologies, thereby refining recurrence risk. However, lack of consensus in terms of testing strategies and methodologies indicates a need for standardized methodology. This study demonstrated CMA results consistent with published karyotype studies established CMA analysis advantages over POC karyotype in all gestational ages. Even in early first-trimester losses, these results support the efficacy of CMA in POC testing.
Objective
To investigate the efficacy and outcomes of chromosomal microarray (CMA) in the cytogenomic evaluation of products of conception (POC).
Method
Over a 42‐month period, 323 POC samples were ...tested by CMA. Results were assessed using variables including phenotype, gestational age, results from orthogonal testing, and follow‐up parental analysis.
Results
CMA identified cytogenetic abnormalities in 47.4% of first trimester losses and 10.9% of second and third trimester losses. Chromosomal microarray results specifically from 5 to 7‐week losses showed similar rates of abnormalities (45.6%) compared to those of all first trimester losses combined. CMA and karyotype results were discordant in 20.0% of cases, most likely due to maternal cell overgrowth in culture. The most prevalent abnormalities identified in all losses were autosomal trisomies, followed by triploidy. In 43/323 cases, the observed abnormality suggested a parental aberration that prompted follow‐up studies; two of these cases indeed identified an inherited aberration.
Conclusion
Our findings of specific types of genetic abnormalities and the respective frequencies by gestational age closely align with those of published karyotype studies, supporting the use of routine CMA testing for POCs. CMA outperforms karyotype analysis because it does not require viable, sterile cultures free of maternal admixture or admixture due to multiple gestations. Finally, CMA results can play an important role in identifying increased recurrence risks for some couples.
Key points
What's already known about this topic?
Cytogenetic analysis of products of conception (POC) reveals cytogenetic abnormalities that can explain pregnancy losses and inform recurrence risks.
POC testing recommendations vary by professional society, with only American College of Obstetricians and Gynecologists recommending routine chromosomal microarray (CMA) a not for early losses.
What does this study add?
CMA increased the overall result yield in cases that could not be analyzed by karyotype.
CMA increased the positive yield, including for early losses, compared with that of karyotype analysis.
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