Molecular genetics and immunohistochemistry characterization of uncommon and recently described renal cell carcinomas

Renal cell carcinoma （RCC） compromises multiple types and has been emerging dramatically over the recent several decades. Advances and consensus have been achieved targeting common RCCs, such as clear cell carcinoma, papillary RCC and chromophobe RCC. Nevertheless, little is known on the characteristics of several newly-identified RCCs, including clear cell （tubulo） papillary RCC, Xpl 1 translocation RCC, t（6;11） RCC, succinate dehydrogenase （SDH）-deficient RCC, acquired cystic disease- associated RCC, hereditary leiomyomatosis RCC syndrome-associated RCC, ALK translocation RCC, thyroid-like follicular RCC, tubulocystic RCC and hybrid oncocytic/chromophobe tumors （HOCT）. In current review, we will collect available literature of these newly-described RCCs, analyze their clinical pathologic characteristics, discuss their morphologic and immunohistologic features, and finally summarize their molecular and genetic evidences. We expect this review would be beneficial for the understanding of RCCs, and eventually promote clinical management strategies.

Major Results and Research Challenges in Cotton Molecular Genetics at CIRAD(France)

CIRAD(Montpellier,France) develops research activities centered on tropical and sub-tropical agricultural systems.Among others crops,cotton is the focus of a series of research programs in different disciplines from economics to breeding.Major areas in genetics and breeding relate to(1) genetic diversity,(2) cultivar development through classical and molecular breeding,and(3)

Molecular genetics of gastric adenocarcinoma in clinical practice

The molecular genetics of gastric carcinoma(GC) dictates their biology and clinical behavior. The two morphologically distinct types of gastric carcinoma by Lauren classification, i.e., intestinal and diffuse cell types, have a significant difference in clinical outcome. These two types of GC have different molecular pathogenetic pathways with unique genetic alterations. In addition to environmental and other etiologies, intestinal type GC is associated with Helicobacter pylori(H. pylori) infection and involves a multistep molecular pathway driving the normal epithelium to intestinal metaplasia, dysplasia, and malignant transformation by chromosomal and/or microsatellite instability(MSI), mutation of tumor suppressor genes, and loss of heterozygosity among others. Diffuse type shows no clear causal relationship with H. pylori infection, but is commonly associated with deficiency of cell-cell adhesion due to mutation of the E-cadherin gene(CDH1), and a manifestation of the hereditary gastric cancer syndrome. Thus, detection of CDH1 mutation or loss of expression of E-cadherin may aid in early diagnosis or screening of diffuse type GC. Detection of certain genetic markers, for example, MSI and matrix metalloproteinases, mayprovide prognostic information, particularly for intestinal type. The common genetic alterations may offer therapeutic targets for treatment of GC. Polymorphisms in Thymidylate synthase to metabolize 5-fluorouracil, glutathione S-transferase for degradation of Cisplatin, and amplification/overexpression of human epidermal growth factor receptor 2 targeted by monoclonal antibody Trastuzumab, are a few examples. P13K/Akt/mT OR pathway, c-Met pathways, epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor fibroblast growth factor receptor, and micro RNAs are several potential therapeutic biomarkers for GC under investigation.

Pathogenic genes associated with Parkinson’s disease:molecular mechanism overview

Parkinson’s disease(PD)is a common neurodegenerative disease in the elderly,accounting for more than 1%of the population aged 65 years.Monogenic inheritance is relatively rare in PD,accounting for approximately 5%to 10%of PD patients,and there is a growing body of evidence suggesting that multiple genetic risk factors play a significant role in the pathogenesis of PD.Several groups have identified and reported a number of genes carrying mutations associated with affected family members.Mutated genes associated with PD are also candidates for idiopathic PD,and these genes may also carry other mutation sites that increase risk.When multiple genetic risk factors are combined,the risk of PD is increased to a greater extent,and to unravel the pathogenic pathways that lead to different forms of PD.This review focuses on the association of PD genes,such as Parkinson Disease 1-24(PARK1-24),glucosylceramidase(GBA),GTP cyclohydrolase 1(GCH1),fibroblast growth factor 20(FGF20),nuclear receptor-related factor 1(NURR1),NUS1 dehydrodolichyl diphosphate synthase subunit(NUS1),diacylglycerol Lipase Beta(DAGLB),transmembrane protein(TMEM),ubiquinol-cytochrome c reductase core protein 1(UQCRC1),glycoprotein non-metastatic melanoma protein B protein(GPNMB),dynactin 1(DCTN1),LDL receptor related protein 10(LRP10),monoamine oxidase(MAO),ataxin 2(ATXN2),microtubule associated protein tau(MAPT),pantothenate kinase 2(PANK2),spastic parapplegia type 11(SPG11),polymer gamma(POLG),TATA-box binding protein associated factor 1(TAF1),dual specificity tyrosine phosphorylation regulated kinase 1A(Dyrk1a),and crystallin alpha A(CRYAA),with the pathogenesis of PD.We introduce what is currently known about the molecular genetics of PD to help explain the molecular mechanisms leading to the neurodegenerative disease.

Molecular genetics of Brugada syndrome

Brugada syndrome(BrS)is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1–V3 and right bundle branch block on electrocardiograms(ECG),and by syncope and sudden death from ventricular tachycardia(VT)and ventricular fibrillation(VF).BrS is responsible for nearly 4%of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries.Since the first diseasecausing gene for BrS(the cardiac sodium channel gene SCN5A)was identified in 1998,extensive investigations on both clinical and basic aspects of BrS have occurred rapidly.SCN5A mutations remain the most common cause of BrS;nearly 300 SCN5A mutations have been identified and are responsible for 20%–30%of BrS cases.Commercial genetic testing is available for SCN5A.Recently,seven other disease-causing genes for BrS have been identified and include GPD1L(BrS2),CACNA1C(Cav1.2,BrS3),CACNB2(Cavβ2,BrS4),SCN1B(Navβ1,BrS5),KCNE3(MiRP2,BrS6),SCN3B(Navβ3,BrS7),and HCN4(BrS8).This article will briefly review the progress made over the past decade in our understanding of the clinical,genetic and molecular aspects of BrS.

Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review

Frontotemporal lobar degeneration(FTLD)represents a group of clinically,neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype.FTLD is pathologically characterized by the frontal and temporal lobar atrophy.Frontotemporal dementia(FTD)clinically presents with abnormalities of behavior and personality and language impairments variants.The clinical spectrum of FTD encompasses distinct canonical syndromes:behavioural variant of FTD(bvFTD)and primary progressive aphasia.The later includes nonfluent/agrammatic variant PPA(nfvPPA or PNFA),semantic variant PPA(svPPA or SD)and logopenic variant PPA(lvPPA).In addition,there is also overlap of FTD with motor neuron disease(FTD-MND or FTD-ALS),as well as the parkinsonian syndromes,progressive supranuclear palsy(PSP)and corticobasal syndrome(CBS).The FTLD spectrum disorders are based upon the predominant neuropathological proteins(containing inclusions of hyperphosphorylated tau or ubiquitin protein,e.g transactive response(TAR)DNA-binding protein 43 kDa(TDP-43)and fusedin-sarcoma protein in neurons and glial cells)into three main categories:(1)microtubule-associated protein tau(FTLD-Tau);(2)TAR DNA-binding protein-43(FTLD-TDP);and(3)fused in sarcoma protein(FTLD-FUS).There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies,which are chromosome 9 open reading frame 72(C9ORF72)gene,granulin(GRN)gene,microtubule associated protein tau gene(MAPT),the gene encoding valosin-containing protein(VCP)and the charged multivesicular body protein 2B(CHMP2B).In this review,recent advances on the different clinic variants,neuroimaging,genetics,pathological subtypes and clinicopathological associations of FTD will be discussed.

Molecular genetic strategies for species identification

This paper probes into the molecular genetic mechanism of the formation of species, subspecies and variety in evolving progression, and brings forward 5 criteria of an ideal strategy in species identification: stating the specific characteristics at species, subspecies and variety level without any interference of too high polymorphism at individual or population level; keys should be distributed as 0 or 1, e. g. yes or no; satisfying repeatability and simple operation; high veracity and reliability; adaptability to widely various specimen. Respectively, this paper reviews two strategies focusing on detecting the fragment length polymorphism and base replacement and lays out some detail methods under above strategies. It demonstrates that it is not possible to solve all species problems by pursuing identification with only a single gene or DNA fragment. Only based on thorough consideration of all strategies, a method or combined several methods could bring satisfying reliability. For advanced focuses, it requires not only development and optimization of methods under above strategies, but also new originality of creative strategies.

Brain Urea as a Potential Biomarker of Neoplasm Progression

Metabolic reprogramming is a key feature driving oncogenesis in cancers. Recent studies have revealed that protein metabolism is largely altered in gliomas facilitating its malignant growth. Urea is the end product of nitrogen metabolism which is mainly produced by arginase. The interdependence of arginase and other biochemical mechanisms triggered scientific research interest. This research aimed to investigate the relationships between the urea as the main parameter of protein metabolism and glioma progression. It was also the most pronounced relationship between urea and the level of the nuclear protein Ki-67 as a marker of proliferative activity and O-6-methylguanine-DNA methyltransferase (MGMT), which performs DNA repair. Postoperative material from 20 patients with gliomas of different grades of anaplasia was analyzed.

Morphological and molecular basis of ovarian serous carcinoma

Serous carcinoma is the most common type of epithelial ovarian cancer. In this review, we provide a com- prehensive picture of ovarian serous cancers from multiple aspects： the first part of this review summarizes the morphological, histological, and immunological signatures of ovarian serous carcinoma; subsequently, we review the history of the evolvement of different grading systems used in ovarian serous cancer; in the end, we focus on characterizing the genetics that underlie the 2-tiered pathways through which ovarian serous cancers are believed to arise： the low-grade and the high-grade pathways.

Genetic classification and molecular mechanisms of primary dystonia

BACKGROUND： Primary dystonia is a heterogeneous disease, with a complex genetic basis. In previous studies, primary dystonia was classified according to age of onset, involved regions, and other clinical characteristics. With the development of molecular genetics, new virulence genes and sites have been discovered. Therefore, there is a gradual understanding of the various forms of dystonia, based on new viewpoints. There are 15 subtypes of dystonia, based on the molecular level, i.e., DYT1 to DYT15. OBJECTIVE： To analyze the genetic development of dystonia in detail, and to further investigate molecular mechanisms of dystonia. RETRIEVAL STRATEGY： A computer-based online search was conducted in PubMed for English language publications containing the keywords ＂dystonia and genetic＂ from January 1980 to March 2007. There were 105 articles in total. Inclusion criteria： ① the contents of the articles should closely address genetic classification and molecular mechanisms of primary dystonia; ② the articles published in recent years or in high-impact journals took preference. Exclusion criteria： duplicated articles. LITERATURE EVALUATION： The selected articles were on genetic classification and molecular genetics mechanism of primary dystonia. Of those, 27 were basic or clinical studies. DATA SYNTHESlS： ① Dystonia is a heterogeneous disease, with a complex genetic basis. According to the classification of the Human Genome Organization, there are 15 dystonia subtypes, based on genetics, i.e., DYT1-DYT15, including primary dystonia, dystonia plus syndrome, degeneration plus dystonia, and paroxysmal dyskinesia plus dystonia.② To date, the chromosomes of 13 subtypes have been localized; however, DYT2 and DYT4 remain unclear. Six subtypes have been located within virulence genes. Specifically, torsinA gene expression results in the DYTI genotype; autosomal dominant GTP cyclohydrolase 1 gene expression and recessive tyrosine hydroxylase expression result in the DYT5 genotype, respectively; the epsilon-sarcoglycan gene is involved in DYT11; Na^＋/K^＋-ATP enzyme α 3 chain gene in DYT12; TATA-conjugated protein-associated factor 1 gene in DYT3; and myofibril regulatory factor gene in DYTS. ③ Different types of dystonia exhibit various clinical characteristics and specific clinical manifestations. ④Many elements regarding the molecular mechanism of dystonia have been determined. However, many components remain poorly understood. For example, detailed pathogenesis remains unclear. Various forms of dystonia exhibit similar problems. Moreover, a single form of dystonia may be a result of two or more different chromosomal mutations. In addition, more studies are needed to fully understand chromosome apposition and virulence genes involved in dystonia. CONCLUSION： The discovery of virulence genes and localizations of newly classified forms of dystonia are beneficial to further understanding the molecular mechanisms of dystonia.

Evolutionary history and phylogeography of Scots pine (Pinus sylvestris L.) in Europe based on molecular markers

In this review we summarized recent historical records and molecular studies on evolutionary history and phylogeography of Scots pine with focus on the European highly fragmented distribution area of the species. Fossilized pollen, plant micro- and macrofossil records provided evidences on the large-scale species’ range shifts and demographic changes during the Quaternary. Populations of Scots pine were documented both in the glacial (incl. full glaciation) and interglacial periods. Recolonization of Europe after the glaciation originated from the (Sub) Mediterranean areas like the Balkan Peninsula but also from around the Eastern Alps and the surroundings of the Danube plain. Fennoscandia and northern European Baltic regions were most probably colonized from two main directions, from Western Europe and from the Russian Plain. Modern history of Scots pine was hardly affected by anthropogenic activities that started to strengthen in the Bronze and Iron Age. Along with the fossil records, molecular genetic tools were used to infer the origin and putative history including migration, differentiation and demography of the species. In this paper we compiled the major publications (30) of molecular genetic studies of the past 20?years derived from distinctly inherited organelle genomes (mitochondrial, chloroplast, nuclear) revealed by different marker systems (mtDNA-cox1, -nad1, -nad3, -nad7, ISSR, cpSSR, nSSR, B-SAP, SNP). It is important to consider that different phylogeographic patterns can be drawn by the analysis of different DNA marker types. Accordingly the use of more than one marker simultaneously outlines the most sophisticated phylogeographical pattern on the genetic lineages and can reveal high differentiation of the European distribution. Combined marker systems and markers derived from coding sequences have also been used to detect species’ phylogeographic patterns, but these were rarely applied to Scots pine. Although new molecular techniques can provide higher resolution data for populations, the reviewed results can shape the direction of further studies.

Rice molecular markers and genetic mapping:Current status and prospects

Dramatic changes in climatic conditions that supplement the biotic and abiotic stresses pose severe threat to the sustainable rice production and have made it a difficult task for rice molecular breeders to enhance production and productivity under these stress factors. The main focus of rice molecular breeders is to understand the fundamentals of molecular pathways involved in complex agronomic traits to increase the yield. The availability of complete rice genome sequence and recent improvements in rice genomics research has made it possible to detect and map accurately a large number of genes by using linkage to DNA markers. Linkage mapping is an effective approach to identify the genetic markers which are co-segregating with target traits within the family. The ideas of genetic diversity, quantitative trait locus（QTL） mapping, and marker-assisted selection（MAS） are evolving into more efficient concepts of linkage disequilibrium（LD） also called association mapping and genomic selection（GS）, respectively. The use of cost-effective DNA markers derived from the fine mapped position of the genes for important agronomic traits will provide opportunities for breeders to develop high-yielding, stress-resistant, and better quality rice cultivars. Here we focus on the progress of molecular marker technologies, their application in genetic mapping and evolution of association mapping techniques in rice.

An estimation of genetic parameters of growth traits in juvenile turbot (Scophthalmus maximus L.) using parental molecular relatedness

The estimation of genetic parameters has played an important role in animal selective breeding for growth traits.Recently studies show that molecular markers can be incorporated into genetic evaluations. In order to improve the performance of an incomplete pedigree（i.e, only parents are known） in the genetic evaluations, 12 microsatellite markers have been applied in the estimation of the genetic parameters for body weight in a farmed population（n=1 890） of juvenile turbot（Scophthalmus maximus L.）. A new relatedness called parental molecular relatedness（PMR） is estimated based on results of genotyping of 48 parents（31 males, 17 females） with microsatellites markers. The feasibility of PMR in estimation of genetic parameters is verified by comparison with pedigree related（PR） which is obtained from a complete pedigree. The results demonstrate that a high correlation（0.872） between them is found. Heritabilities are estimated using the PMR（0.52±0.13） and PR（0.55±0.22） with the same animal model. A cross-validation shows that the predictive abilities of models using the PMR and the PR are identical（0.81）. From that, a conclusion can be made that PMR and PR predicted genetic values equally well in a population of juvenile turbot. Therefore PMR can be applied as an alternative of the PR when only parents are known. However, for a better performance, more markers and more families should be included in a further study.

Molecular Genetic Analysis of Partial 9p Trisomy in Two Chinese Families with Mental Retardation and Facial Anomaly

Mental retardation is defined by significant limitations in intellectual function and adaptive behavior that occur before 18 years of age.Many chromosomal diseases come with mental retardation.We reported two Chinese families with partial trisomy 9p and other chromosome partial monosomy,clinical features of mental retardation and mild facial and pinkie anomalies.In the family 1,we showed that the proband carried a trisomy 9p21.3→pter and monosomy 21q22.3→qter by using fluorescence in situ hybridization analysis.Molecular genetic analysis defined the precise breakpoint on chromosome 9p between markers D9S1846 and D9S171,an interval of about 2.9 Mb on 9p21.3,and the breakpoint on chromosome 21q between markers D21S1897 and D21S1446,a region of about 1.5 Mb on 21q22.3.In the family 2,a patient with trisomy 9p21.3→pter and monosomy 5p15.33→pter,and a de novo maternal balanced translocation between chromosomes 5 and 9 was identified in his mother.Cytogenetic and molecular genetic analysis defined the precise breakpoints on chromosome 9p21.3 and chromosome 5p15.33.Further clinical investigation found that any individual had no refractoriness eczema disease except the proband in this family.These results further implicate that trisomy 9p is associated with mental retardation,and that there may be key gene duplication on chromosome 9p21.3→9pter responsible for mental retardation and mild facial anomaly.This result has been applied successfully in prenatal diagnosis of the second family.

Genetic Analysis of Cotton Fiber Traits by Molecular Markers

1.Development of EST-SSRs derived from G.barbadense:One hundred and nineteen EST-SSRs were developed based on 98 unique ESTs from a cDNA library constructed in our laboratory using developing fibers from G.barbadense cv.3-79.Among the SSRs,trinucleotide AAG appeared

Novel homozygous ADAMTS17 missense variant in Weill-Marchesani syndrome

AIM: To explore the phenotype and genotype of WeillMarchesani syndrome(WMS) in a Chinese family and review related literature.METHODS: Three WMS patients and other unaffected individuals in this family with a history of consanguineous marriage were included in this study. Medical history, comprehensive ophthalmic examinations, and systemic evaluation, as well as whole exome and Sanger sequencing of specific genomic regions, were performed. RESULTS: The three affected siblings presented with short stature, brachydactyly and ocular disorders, including very shallow anterior chamber, high myopia, microspherophakia lens subluxation with stretched zonules and glaucoma. Genetic analysis verified a homozygous missense mutation(c.2983C>T: p. Arg995Trp) in ADAMTS17,which was correlated with the diseases in this family, indicating an autosomal recessive inherited manner of WMS. This review aims to summarize the mutation sites of WMS genes, so as to prevent the disease and better guide clinical diagnosis and treatment.CONCLUSION: A novel homozygous missense variant of ADAMTS17 is identified in a WMS family with a history of consanguineous marriage. Our study expands the range of mutations associated with WMS and deepens our understanding of pathology in disease associated with ADAMTS17 variants.

Eosinophil disorders:an update on diagnosis and management

Eosinophilia can be seen in almost all medical subspecialty patients.Delay in diagnostic workup and treatment is associated with significant morbidity and mortality.Clinical vigilance and timely referral for diagnostic evaluation are critical.Causes of hypereosinophilia(HE)are diverse and can be grouped under 3 categories:primary(neoplastic),secondary(reactive),and idiopathic.Advances in molecular genetic diagnostics have led to elucidation of the genetic basis formany neoplastic hypereosinophilic disorders.One commonmolecular feature is formation of a fusion gene,resulting in the expression of an aberrantly activated tyrosine kinase(TK).TheWorld Health Organization endorsed a biologically oriented classification scheme and created a new major disease category,namely,myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions.Rearrangement of other TK genes and activating somatic mutation(s)in TK genes have also been reported in eosinophilic neoplasms.Diagnostic evaluation of HE involves a combination of clinical,histopathologic,and immunophenotypic analyses,as well as molecular genetic testing,including next-generation sequencing–based mutation panels.The management of primary HE is largely guided by the underlying molecular genetic abnormalities.Good knowledge of recent advances in HE is necessary to ensure timely and accurate diagnosis and to help optimize patient care.

Role of the Pentanucleotide (tttta)_n Polymorphisms of CYP11αGene in the Pathogenesis of Hyperandrogenism in Chinese Women with PolycysticOvary Syndrome

Summary: To determine the (tttta) n repeat polymorphisms at the promoter region of CYP11α gene, and study its linkage to hyperandrogenism of polycystic ovary syndrome (PCOS) in Chinese women, a case-control study was conducted in the Reproductive Medical Center of the Second Affiliated Hospital of Zhengzhou University (Zhengzhou, China). 96 PCOS patients and 78 healthy control women were included. CYP11α (tttta) n repeat-polymorphism genotyping analysis was performed by using polymerase chain reaction (PCR). Serum pituitary hormone and total testosterone levels were measured by ELISA. 4 different CYP11α (tttta) n allelles were identified, corresponding to 4-, 6-, 8-, and 9-repeat-unit alleles. The frequency and distribution of these alleles are 0.16, 0.33, 0.38, and 0.13 respectively in PCOS patients, as compared with 0.20, 0.34, 0.35, and 0.11 respectively in healthy controls. There were no significant differences between these two groups. Moreover, no correlation between the polymorphism of CYP11α gene and serum testosterone level of patients with PCOS and controls was observed. It is concluded that microsatellite polymorphism (tttta) n of gene CYP11α exists in Chinese women and the polymorphism of CYP11α gene does not play an important role in the pathogenesis of Chinese patients with PCOS, especially in patients with hyperandrogenism.