Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma

Objective:To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma,offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions.Methods:A total of 282 patients with gastric adenocarcinoma(182 males and 100 females)were enrolled in this study,with peripheral blood genomic DNA extracted.Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing.Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics(ACMG)guidelines.Results:In this study,7.1%(20/282)of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes.The detection rate in male patients(3.8%,7/182)was significantly lower than that in female patients(13%,13/100)(P=0.004).The most recurrent mutations were in AT mutated(ATM)(1.1%,3/282),followed by BRCA1,BRIP1 and RAD51D,all showed a detection rate of 0.7%(2/282).Mutations in three genes associated with hereditary gastric cancer syndromes were detected,namely,PMS2 and EP CAM associated with Lynch syndrome and CDH1 associated with hereditary di ffuse gastric cancer.The detection frequencies were all 0.4%(1/282).Notwithstanding no significant difference observed,the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers(median age:58.5 vs.60.5 years old),while the age of patients with ATM mutations was the youngest overall(median age:49.3 years old).Conclusions:Our study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes,and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significandy lower than that in female patients.Some known and unidentified mutations were found in gastric cancer,which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.

Child with adenylosuccinate lyase deficiency caused by a novel complex heterozygous mutation in the ADSL gene:A case report

BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.

A Novel HSF4 Mutation in a Chinese Family with Autosomal Dominant Congenital Cataract

This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4（HSF4） gene in a Chinese family with autosomal dominant congenital cataract（ADCC）. All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism（RFLP） analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C〉T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.

Antibody-Like Phosphorylation Sites in Focus of Statistically Based Bilingual Approach

In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequently, we look here for the sequences 1) composing human and mouse proteins different from antigen receptors, 2) identical with or highly similar to nucleotide sequence representatives of conserved variable immunoglobulin segments and 3) identical with or closely related to phosphorylation sites. More precisely, we searched for the corresponding actual pairs of DNA and protein sequence segments using five-step bilingual approach employing among others a) different types of BLAST searches, b) two in-principle-different machine-learning methods predicting phosphorylated sites and c) two large databases recording existing phosphorylation sites. The approach identified seven existing phosphorylation sites and thirty-seven related human and mouse segments achieving limits for several predictions or phylogenic parameters. Mostly serines phosporylated with ataxia-telangiectasia-related kinase (involved in regulation of DNA-double-strand-break repair) were indicated or predicted in this study. Hypermutation motifs, located in effective positions of the selected sequence segments, occurred significantly less frequently in transcribed than non-transcribed DNA strands suggesting thus the incidence of mutation events. In addition, marked differences between the numbers and proportions of human and mouse cancer-related sequence items were found in different steps of selection process. The possible role of hypermutation changes within the selected segments and the observed structural relationships are discussed here with respect to DNA damage, carcinogenesis, cancer vaccination, ageing and evolution. Taken together, our data represent additional and sometimes perhaps complementary information to the existing databases of empirically proven phosphorylation sites or pathogenically important spots.

2+0 CYP21A2 deletion carrier—a limitation of the genetic testing and counseling:A case report

BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.

先导编辑的研究进展及应用前景

人类众多遗传性疾病是由于基因组突变所导致,而基于基因编辑技术的基因治疗策略,可从DNA层面对致病突变进行彻底修复,为疾病的治愈提供了新的可能.随着基因编辑技术的不断发展与突破,2019年新型DNA编辑工具先导编辑(PE)成功问世.PE技术并不会引起DNA双链断裂(DSBs),也无需单独引入DNA模板,即可实现基因编辑,可广泛应用于包括点突变及小片段的插入、删除等不同场景.与传统基因编辑工具相比,PE因其高编辑效率及低脱靶率,具备更高的有效性与安全性.本篇综述:(1)详细介绍了先导编辑的工作原理及发展历史.(2)概述了先导编辑系统的改良策略,包括相关酶的改造、工具RNA的结构改进以及递送方式的创新(3)梳理了辅助PE系统设计和分析的网页工具,简化了PE系统的搭建及使用流程.(4)系统总结了PE在疾病模型中的应用案例,并展望了未来的临床应用前景.