Sporadic somatic mutation of c-kit gene in a family with gastrointestinal stromal tumors without cutaneous hyperpigmentation

没有皮肤的亢奋的色素沉着，我们与胃肠的基质肿瘤(大意) 在一个家庭描述了二个成员。病人是没有皮肤的亢奋的色素沉着的父亲和儿子。组织学的检查证明这些肿瘤是表示 CD34 和 CD117 的大意。从嵌入石蜡的标本提取的肿瘤 DNA 在直接定序分析以后在 11 c 工具包基因上在前在不同鳕鱼 ons 与一个删除变化揭示了体细胞突变。没有细菌线变化在从从父亲和儿子获得的外部白血球提取的 DNA 被检测。我们建议没有细菌线变化和亢奋的色素沉着，大意能被分散的体细胞突变在一个家庭引起。

Mutational screening of affected cardiac tissues and peripheral blood cells identified novel somatic mutations in GATA4 in patients with ventricular septal defect

The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.

Somatic cell mutations in cerebral tissue of cattle affected by bovine spongiform encephalopathy

In animals the prion disease includes sheep and goat scrapie and the bovine spongiform encephalopathy (BSE). While several polymorphisms of the prion (PRNP) gene have been identified in sheep and some of them have been associated with susceptibility to scrapie, few mutations are reported in cattle and no correlation with BSE have been demonstrated. Genetic screening for mutants in the PRNP gene of 21 BSE positive animals by direct sequencing of the amplified gene, using DNA extracted from brain as template, confirmed that only few polymorphisms are present. However DNA molecules cloned and sequenced from the population of fragments considering a total of 90 clones from 9 BSE positive and 70 clones from 7 BSE negative animals, gave a highly significant differences in the frequency of mutations (p = 0.01). The high frequency and type of variants found cannot be explained only with misincorporation error of the Taq polymerase. Interestingly one of the mutations found in the BSE positive animals (F209S) corresponds to a mutant that causes a familiar form of prion disease in humans (F198S). These data can be explained with the presence of somatic mutations modifying the PRNP gene in single brain cells.

Somatic TP53 mutations and comparison of different TP53 functional domains in human cancers:data analysis from the IARC TP53 database and the National Cancer Institute GDC data portal

P53 gene mutations have been known to be highly related to the majority of human cancers.The colocation of biologists and bioinformaticians have constructed many databases for cancer research.Although the relationship between the presence of TP53 mutation and cancers has been reported in various studies,few reports TP53 mutation distribution in different functional domains.Hence,we use 2 databases(The TP53 Mutation Database of the International Agency for the Research on Cancer and The Genomic Data Commons data portal)to compare survival rate with and without TP53 mutations in a certain cancer,as well as to find most frequent mutation sites in different functional domains of the TP53 protein.Our study shows that most somatic mutations of TP53 and high mutation rate sites are concentrated in the DNA-binding domain,and the survival of certain cancers varies with and without P53.

Mutational separation and clinical outcomes of TP53 and CDH1 in gastric cancer

BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.

Androgen receptor signaling and mutations in prostate cancer

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression

Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA(mtDNA).In the past decades,several types of somatic mtDNA alterations have been identified in gastric cancer.However,the role of these mtDNA alterations in gastric cancer progression remains unclear.In this review,we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer.The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed.We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers.The two primary mutation types(transition mutations and mononucleotide or dinucleotide repeat instability)imply potential causative factors.Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer.The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.

Identification of EGFR kinase domain mutations among lung cancer patients in China:implication for targeted cancer therapy

Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

The emerging role of somatic tumor sequencing in the treatment of urothelial cancer

The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies.Whole exome sequencing has highlighted the individualistic nature of malignancies on a patient-to-patient basis and begun to revolutionize therapeutic approaches.In recent years,whole genome sequencing of urothelial malignancies has identified a host of somatic mutations which contribute to growth,progression,and metastasis of urothelial carcinoma of the bladder and upper tract urothelial carcinoma.As genetic sequencing continues,additional targets will be identified,allowing development of novel therapeutic agents targeting cancer on a molecular level,with the goal of delivering highly individualized care based on the underlying mutational profile of the patient’s malignancy.In this review,we aim to discuss known genetic alterations of urothelial malignancy and the implications these mutations carry in terms of prognostication and development of targeted therapeutic agents.We will focus on RNA-expression profiling and genomic DNA profiling,with a focus on comprehensive whole exome and whole genome sequencing relative to selected urothelial carcinoma-associated genes and circulating tumor DNA analysis.

常山柚橙不同树龄和繁殖方式的遗传变异分析

本研究以20~100年实生和嫁接的常山柚橙(Citrus×aurantium L.‘Changshanhuyou’)为材料,进行全基因组背景分析、体细胞变异检测和果实品质评价。结果显示,常山柚橙与药用枳壳基原品种黄皮酸橙(C.aurantium L.‘Huangpi’)、代代花(C.aurantium L.‘Daidai’)、朱栾(C.aurantium L.‘Chuluan’)和塘橙(C.aurantium L.‘Tangcheng’)聚类在一起,两者与酸橙(C.aurantium L.)的遗传相似度在76.99%~91.06%。随着常山柚橙树龄的增加,其果实品质发生变化,且体细胞变异总数增加。枳(Poncirus trifoliata(L.)Raf.)砧不会改变常山柚橙的果实品质,但其接穗中体细胞变异总数增加,其中变异基因涉及衰老修复和逆境防御过程。综上所述,常山柚橙是酸橙变种,且在常规生产年限内,其果实品质稳定,遗传物质保持不变,但体细胞变异数量逐渐积累。

全外显子测序揭示原发中枢神经系统淋巴瘤的基因突变特征

目的:对18例原发中枢神经系统淋巴瘤(PCNSL)患者肿瘤组织进行全外显子测序,探索PCNSL的基因突变特点。方法:收集2018年9月至2020年12月在兰州大学第二医院病理科确诊的18例免疫功能正常(无HIV及服用免疫抑制剂病史)、病理类型为弥漫大B细胞淋巴瘤的PCNSL患者肿瘤组织,进行基于高通量测序的全外显子测序,平均测序深度>100×。测序结果经数据处理及生物信息学分析,得到患者的基因突变全景及突变特征。结果:18例患者均检测到明显的体细胞突变,中位体细胞突变数目为321,以错义突变为主(约占90%),突变类型以C>T为主(占50.2%),反映了与年龄相关的突变模式;前15位高频突变基因中,PSD3、DUSP5、MAGEB16、TELO2、FMO2、TRMT13、AOC1、PIGZ、SVEP1、IP6K3、TIAM1为驱动基因。驱动基因通路富集结果显示,RTK-RAS、Wnt、NOTCH、Hippo、Cell-Cycle通路明显富集。各样本的肿瘤突变负荷在3.558 48/Mb-8.780 89/Mb之间,平均突变负荷4.953 32/Mb,与TCGA数据库中其他肿瘤的研究队列相比明显增高。结论:PCNSL频繁发生体细胞的错义突变,以点突变为主,突变类型主要为C>T。驱动基因主要参与RTK-RAS、Wnt、NOTCH、Hippo通路信号传导,表明以上通路可能与PCNSL发病机制相关。PCNSL有显著的高肿瘤突变负荷,这或许是PD-1抑制剂治疗PCNSL有效的原因之一。

血管内皮细胞体细胞突变与脑血管畸形

脑血管畸形(cerebral vascular malformations,CVMs)是指脑血管在胚胎时期因各种内、外界因素的影响,导致基因、细胞因子和蛋白等发生改变而引起的脑局部血管数量和结构的非肿瘤性发育异常所导致的疾病。血管内皮细胞基因突变作为关键始动因素之一,在CVMs的发生发展中起到了重要作用。了解CVMs中存在的内皮细胞突变对于预防其发生发展,开发靶向药物及指导临床治疗具有重要意义。本文将针对血管内皮细胞体细胞突变在CVMs中的发现、临床相关性及潜在的治疗意义进行综述。

先天性黑素细胞痣的发病机制及诊疗策略

先天性黑素细胞痣(Congenital melanocytic nevi,CMN)是一种常见的皮肤发育异常,可发生于人体任何有黑素细胞存在的部位。其发生与体细胞突变密切相关,受多种信号通路调控,临床表现多样。手术切除、扩张器应用仍是治疗CMN的主要方式,光电治疗是消除色素、清除卫星灶的有力手段。靶向、免疫治疗正成为治疗先天性黑色素巨痣的新方向。

克隆性造血与心血管疾病相关性的研究进展

造血系统中体细胞突变的非恶性克隆扩增被称为克隆性造血,是在驱动基因突变后突变白细胞比例增加的过程。克隆性造血的遗传模式包括白血病驱动基因突变、常染色体镶嵌染色体交替和性染色体缺失。新近研究指出,由白血病驱动基因突变或白细胞Y染色体镶嵌缺失引起的克隆性造血,会影响各种心血管疾病(包括动脉粥样硬化、心力衰竭、心脏纤维化)的发生发展。越来越多的证据表明,克隆性造血是心血管疾病的一种新机制,也是一类新的危险因素,与传统危险因素同等重要。现分析克隆性造血的遗传模式,对其与心血管疾病之间的相关性展开综述分析。

A new era of mutation rate analyses: Concepts and methods

The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate research.This paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation rates.It examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary hypotheses.Furthermore,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and tissues.Finally,it proposes several potential research directions and pressing questions for future investigations.

Failure to Identify Somatic Mutations in Monozygotic Twins Discordant for Schizophrenia by Whole Exome Sequencing

Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.

The etiology,clinical features and medical treatment of somatotroph adenomas

Somatotroph adenomas lead to hypersecretion of growth hormones(GH)and may cause mass effects.Patients with somatotroph adenomas may present with acral and soft tissue enlargement,joint pain,heart and respiratory failure,diabetes mellitus and hypertension,resulting in increased morbidity and mortality.Early diagnosis and treatment are therefore important in prolonging life and improving quality of life.Recent studies depicted the landscape of genetic and epigenetic changes in sporadic somatotroph adenomas.New approaches are being developed for genetic testing,diagnosis and surveillance,which are helpful in early diagnosis,treatment and disease control of somatotroph adenomas.Data suggest that patients with somatotroph adenomas are best treated with multidisciplinary teams composed of neuro-endocrinologists,neurosurgeons,radiation oncologists and other specialists.This mini-review summarizes in a concise way the up-to-date discussion on the etiology,new diagnostic techniques and novel treatments of somatotroph adenomas.

尿路上皮体细胞突变在膀胱肿瘤发生和复发中作用的研究进展

膀胱肿瘤具有高发病率、高复发率等特点,但其发生和发展,特别是易复发的具体机制仍不明了。本文从膀胱癌分子特征、尿路上皮体细胞突变景观、驱动基因及突变特征等方面来阐述尿路上皮体细胞突变在膀胱肿瘤发生、复发中的作用及机制,并对下一步的研究方向进行展望。

前列腺癌体系突变及治疗研究进展

前列腺癌是目前全球最常见的男性恶性肿瘤之一,严重威胁中老年男性健康。前列腺癌患者的临床表现和疾病预后具有个体差异,低危患者病程缓慢,死亡风险较低,而中高危患者预后较差,死亡风险较高。目前研究表明,前列腺癌的临床表现与基因突变相关,而体系突变作为前列腺癌基因突变的重要组成部分,与肿瘤的发生转移相关,可作为前列腺癌患者危险分级预后预测的潜在依据。本文就前列腺癌体系突变及治疗研究进展作一综述,以期为该疾病的诊断治疗提供借鉴。