Relationship Between Gene-Phenotype and Clinical Manifestations of Chromosomal Copy Number Variations Indicated by Non-Invasive Prenatal Testing

Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.

Extracellular control of chromosomal instability and maintenance of intra-tumoral heterogeneity

Aim:Current cancer treatments are challenged by the plasticity of cancer cells,largely influenced by chromosomal instability(CIN)leading to variations in karyotype known as tumor-specific aneuploidy,which in turn,leads to intra-tumor cellular heterogeneity(TH).Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors.Modulation of the CIN rate seems to reside within the tumor itself.In an attempt to develop a therapy targeting cancer plasticity,we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.Methods:Chr7-fluorescence in situ hybridization was applied on various grades of gliomas,in vitro cultures and intracranial xenografts of two syngeneic glioma lines(U251 and U251-NS)derived from various cell-inoculating densities,with or without EFEMP1 overexpression.Results:A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas.A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.Conclusion:Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells,and EFEMP1 is one of these factors.