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Whole exome sequencing reveals novel somatic alterations in neuroblastoma patients with chemotherapy.

ABSTRACT: We ought to explore the acquired somatic alterations, shedding light on genetic basis of somatic alterations in NB patients with chemotherapy.Marrow blood samples from NB patients were collected before treatment, after the 2nd and 4th chemotherapy for baseline research and continuous monitoring by whole exome sequencing. Plasma cell free DNA (cfDNA) was prepared for baseline research. Finger nail cells were extracted as self control. The clinical data was analyzed.From December 2014 to February 2016, 27 cases of children with stage IV NB were diagnosed. The follow up time ranged from 5 to 25 months, with a median follow up time of 17 months, 20 patients were stable, one patient died of pulmonary embolism during surgery, six patients died of disease progression. Marrow blood whole exome sequencing demonstrated that several novel somatic mutations were identified in all three trios comply or against the trendy of tumor size variation. Of note, six recurrent mutations in bromodomain PHD finger transcription factor (BPTF) were identified in nine NB patients under the continuous monitoring. The mutation rates variation was positively correlated to tumor size (CC = 0.428, P = 0.021), and patients with BPTF mutation may have a worse prognosis compared with wild type. Meanwhile, CGREF1, CUX2, GP1BA, SLC45A1 and TRA2A were mutated with the trendy oppose as therapeutic effects. The baseline research in three NB patients demonstrated that mutation rate of BPTF, TMCO3, GPRIN2 and C20orf96 in plasma cfDNA were in positive correlation with bone marrow genomic DNA (P = 0.001).Our study showed that BPTF along with other mutations may function as a biomarker for evaluating to effects of chemotherapy to this refractory tumor, and patients with BPTF mutation might have a worse prognosis.

SUBMITTER: Duan C

PROVIDER: S-EPMC5816515 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Whole exome sequencing reveals novel somatic alterations in neuroblastoma patients with chemotherapy.

Duan Chao C Wang Han H Chen Ying Y Chu Ping P Xing Tianyu T Gao Chao C Yue Zhixia Z Zheng Jie J Jin Mei M Gu Weiyue W Ma Xiaoli X

Cancer cell international 20180217

<h4>Background</h4>We ought to explore the acquired somatic alterations, shedding light on genetic basis of somatic alterations in NB patients with chemotherapy.<h4>Methods</h4>Marrow blood samples from NB patients were collected before treatment, after the 2nd and 4th chemotherapy for baseline research and continuous monitoring by whole exome sequencing. Plasma cell free DNA (cfDNA) was prepared for baseline research. Finger nail cells were extracted as self control. The clinical data was analy ...[more]

PMID: 29467591

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Project description:ObjectiveHypophosphatemic rickets (HR) is a heterogeneous genetic phosphate wasting disorder. The disease is most commonly caused by mutations in the PHEX gene located on the X-chromosome or by mutations in CLCN5, DMP1, ENPP1, FGF23, and SLC34A3. The aims of this study were to perform molecular diagnostics for four patients with HR of Indian origin (two independent families) and to describe their clinical features.MethodsWe performed whole exome sequencing (WES) for the affected mother of two boys who also displayed the typical features of HR, including bone malformations and phosphate wasting. B-lymphoblast cell lines were established by EBV transformation and subsequent RT-PCR to investigate an uncommon splice site variant found by WES. An in silico analysis was done to obtain accurate nucleotide frequency occurrences of consensus splice positions other than the canonical sites of all human exons. Additionally, we applied direct Sanger sequencing for all exons and exon/intron boundaries of the PHEX gene for an affected girl from an independent second Indian family.ResultsWES revealed a novel PHEX splice acceptor mutation in intron 9 (c.1080-3C>A) in a family with 3 affected individuals with HR. The effect on splicing of this mutation was further investigated by RT-PCR using RNA obtained from a patient's EBV-transformed lymphoblast cell line. RT-PCR revealed an aberrant splice transcript skipping exons 10-14 which was not observed in control samples, confirming the diagnosis of X-linked dominant hypophosphatemia (XLH). The in silico analysis of all human splice sites adjacent to all 327,293 exons across 81,814 transcripts among 20,345 human genes revealed that cytosine is, with 64.3%, the most frequent nucleobase at the minus 3 splice acceptor position, followed by thymidine with 28.7%, adenine with 6.3%, and guanine with 0.8%. We generated frequency tables and pictograms for the extended donor and acceptor splice consensus regions by analyzing all human exons. Direct Sanger sequencing of all PHEX exons in a sporadic case with HR from the Indian subcontinent revealed an additional novel PHEX mutation (c.1211_1215delACAAAinsTTTACAT, p.Asp404Valfs*5, de novo) located in exon 11.ConclusionsMutation analyses revealed two novel mutations and helped to confirm the clinical diagnoses of XLH in two families from India. WES helped to analyze all genes implicated in the underlying disease complex. Mutations at splice positions other than the canonical key sites need further functional investigation to support the assertion of pathogenicity.

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Whole exome sequencing reveals novel somatic alterations in neuroblastoma patients with chemotherapy.

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Whole exome sequencing reveals novel somatic alterations in neuroblastoma patients with chemotherapy.

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