Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a deadly disease with limited options for targeted therapy. With the help of next-generation sequencing studies over the last decade, we gained an understanding of the genomic architecture of EAC. The tumor suppressor gene TP53 is mutated in 70 to 80% of tumors followed by genomic alterations in CDKN2A, KRAS, ERBB2, ARID1A, SMAD4 and a long tail of less frequently mutated genes. EAC is characterized by a high burden of point mutations and genomic rearrangements, resulting in amplifications and deletions of genomic regions. The genomic complexity is likely hampering the efficacy of targeted therapies. Barrett’s esophagus (BE), a metaplastic response of the esophagus to gastro-esophageal reflux disease, is the main risk factor for the development of EAC. Almost all EACs are derived from BE. The sequence from BE to EAC provides an opportunity to study the genomic evolution towards EAC. While the overlap of point mutations between BE and EAC within the same patient is, at times, surprisingly low, there is a correlation between the complexity of the genomic copy number profile and the development of EAC. Transcriptomic analyses separated EAC into a basal and a classical subtype, with the basal subtype showing a higher level of resistance to chemotherapy. In this review, we provide an overview of the current knowledge of the genomic and transcriptomic characteristics of EAC and their relevance for the development of the disease and patient care.

Unraveling the Wide Spectrum of Melanoma Biomarkers

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow’s original report on “melanoma and prognostic values of thickness”, providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia

Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated. Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs. Intriguingly, a misfolded p53 was described in AML blasts that do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a pseudo-mutant conformations of p53. By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudo-mutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent. Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing. Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.

Association between tobacco substance usage and a missense mutation in the tumor suppressor gene P53 in the Saudi Arabian population

The tumor suppressor gene TP53 and its downstream genes P21 and MDM2 play crucial roles in combating DNA damage at the G1/S cell cycle checkpoint. Polymorphisms in these genes can lead to the development of various diseases. This study was conducted to examine a potential association between tobacco substance usage (TSU) and single-nucleotide polymorphism (SNP) at the exon regions of the P53, P21, and MDM2 genes by comparing populations of smokers and non-smokers from Saudi Arabia. P53 rs1042522 (C/G), P21 rs1801270 (A/C), and MDM2 rs769412 (A/G) were investigated by genotyping 568 blood specimens: 283 from male/female smokers and 285 from male/female non-smokers. The results obtained from the smokers and their control non-smokers were compared according to age, sex, duration of smoking, and type of TSU. Heterozygous CG, homozygous GG, and CG+GG genotypes, as well as the G allele of rs1042522 were significantly associated with TSU in Saudi smokers compared with non-smokers. The C allele frequency of rs1801270 was also associated with TSU in smokers (OR = 1.33, p = 0.049) in comparison with non-smokers, in younger smokers (≤29 years) (OR = 1.556, p = 0.03280) in comparison with non-smokers of the same age, in smokers who had smoked cigarettes for seven years or less (OR = 1.596, p = 0.00882), and in smokers who had consumed shisha (OR = 1.608, p = 0.04104) in comparison with the controls. However, the genotypic and allelic frequencies for rs769412 did not show significant associations with TSU in Saudis. The selected SNP of P53 was strongly associated with TSU and may be linked to TSU-induced diseases in the Saudi Arabian population.

Meduloblastoma pediatrikoaren pronostikorako markatzaile molekularren identifikazioa

Meduloblastoma klinika eta oinarri molekular heterogeneoa duen minbizia da. Azken urteotan, genoma osoko eta sekuentziazio masiboko teknika molekularren garapenaren ondorioz, meduloblastoma pediatrikoan parte hartzen duten mutazio asko identifikatzea ahalbidetu da. Hortaz, lanaren helburua izan zen meduloblastoma pediatrikoaren pronostikoan edota terapian lagundu dezakeen gene eta mutazio somatikoen panel baten diseinua egitea. Horretarako, meduloblastoma pediatrikoan eragina duten geneei buruzko informazioa duen literaturaren berrikuspen sistematikoa egin zen. Bilaketarako Pubmed datubase bibliografikoa erabili zen honako termino hauek erabiliz: (Medulloblastoma*) AND (“mutation*” OR “genetic alteration*” OR “genetic variation*”). Berrikuspen bibliografikoaren ondoren, hasieran zeuden 588 artikuluetatik 62 artikulutan 197 gene identifikatu ziren. Horietatik, % 2 baino gehiagoko mutazio-maiztasuna zuten 21 gene aurkitu ziren, eta diagnosiaren momentuan balio pronostikoa edo meduloblastoma azpimoten ezaugarri ziren 5 gene (TP53, CTNNB1, PTCH1, SUFU eta KDM6A) aurkitu ziren. Gene horiek analizatuz gero, profil molekularrean oinarritutako tratamendu indibidualizatuak doitu litezke.

Identifying regions of a gene that are susceptible to mutation

In this article, the susceptibility of any gene to mutation is explained through the tumor suppressor gene TP53 using the concept of the energy of a graph. We considered the structure of TP53 gene as a weighted graph where the weights are the bond dissociation energies. We computed energies of each exon and investigated how they distributed over the bases. We observed that exons 4 and 12 have unusual energy distributions compared to other exons. The energy was found to be signifi- cantly reduced relative to other regions between the 44th and 47th codons of exon 4, and this is in line with the literature results to which these regions are subject to severe missense and frameshift mutations. The energy of exon 12 changes very rapidly at very short intervals and is not consistently distributed across the exon. The excited energy probability distribution of exon 9 is used to determine the most vulnerable region of exon 9 when subjected to any physical or chemical external influences.

The Relationship of Gliomas with Tp53 Rs1042522 C > G And Gliomas in Duhok

A tumor suppressor gene TP53 has a central role in controlling the cell cycle, apoptosis, as well as DNA damage repair. A common polymorphism in TP53 is the Arg72Pro exon 4 polymorphism. Polymorphism has been proposed to be associated with genetically determined susceptibility in different types of cancers, including glioma. This study was conducted to estimate the distribution of glioma within age groups, gender, smokers, and residence of individual also to investigate the distribution of TP53 Arg72Pro SNPs genotype in glioma, and determine whether TP53 Arg72Pro polymorphism is a possible relevance in susceptibility to glioma using RFLP-PCR analysis. Enrolled were 65 patients (glioma tissues matched age and gender) and 70 healthy individuals as a control. The findings in glioma samples 40(61.54%) were homozygous for arginine (Arg / Arg), 19 (29.23%) heterozygous for (Arg / Pro), and 6 (9.23%) homozygous for proline (Pro / Pro). Three separate frequencies of genotypes of Arg72Pro; 33 (47.14%), 28 (40.0), and 9 (12.86%) were identified in healthy individuals, respectively. The allele Frequencies for the Pro 72 and Arg 72 gliomas were 16 (24.62%) and 49 (75.38%), respectively. In the Pro 72 and Arg 72 controls, the allele frequencies were 23 (32.86%) and 47 (67.14%), respectively. Finally, there was no significant relationship between age group, gender, dwellers, non-smokers and smokers in different genotypes of codon 72 of TP53 gene (P < 0.05).

The Relationship of Gliomas with Tp53 Rs1042522 C > G And Gliomas in Duhok

A tumor suppressor gene TP53 has a central role in controlling the cell cycle, apoptosis, as well as DNA damage repair. A common polymorphism in TP53 is the Arg72Pro exon 4 polymorphism. Polymorphism has been proposed to be associated with genetically determined susceptibility in different types of cancers, including glioma. This study was conducted to estimate the distribution of glioma within age groups, gender, smokers, and residence of individual also to investigate the distribution of TP53 Arg72Pro SNPs genotype in glioma, and determine whether TP53 Arg72Pro polymorphism is a possible relevance in susceptibility to glioma using RFLP-PCR analysis. Enrolled were 65 patients (glioma tissues matched age and gender) and 70 healthy individuals as a control. The findings in glioma samples 40(61.54%) were homozygous for arginine (Arg / Arg), 19 (29.23%) heterozygous for (Arg / Pro), and 6 (9.23%) homozygous for proline (Pro / Pro). Three separate frequencies of genotypes of Arg72Pro; 33 (47.14%), 28 (40.0), and 9 (12.86%) were identified in healthy individuals, respectively. The allele Frequencies for the Pro 72 and Arg 72 gliomas were 16 (24.62%) and 49 (75.38%), respectively. In the Pro 72 and Arg 72 controls, the allele frequencies were 23 (32.86%) and 47 (67.14%), respectively. Finally, there was no significant relationship between age group, gender, dwellers, non-smokers and smokers in different genotypes of codon 72 of TP53 gene (P < 0.05).

Vliyaniye modulyatsii aktivnosti r53 na vzaimodeystviye chlenov semeystva r53 v protsesse differentsirovki keratinotsitov linii NaSaT

Kletki linii HaCaT yavlyayutsya rasprostranennoy model'yu dlya issledovaniya normal'nykh keratinotsitov cheloveka. Odnako dlya kletok etoy linii kharakterny mutatsii v gene TP53, chto sushchestvenno skazyvayetsya na funktsiyakh kodiruyemogo belka. Osobennosti dannogo regulyatornogo kontura neobkhodimo uchityvat' pri ispol'zovanii kletok HaSaT v kachestve ob"yekta issledovaniy fiziologii i patologii kozhi cheloveka in vitro. Tsel'yu issledovaniya bylo izuchit' osobennosti realizatsii programmy differentsirovki v kletkakh linii HaCaT v usloviyakh modulyatsii aktivnosti belka r53. Snizheniya urovnya ekspressii r53 dobivalis' nokdaunom gena TR53 s pomoshch'yu shRNA (v 2,2 raza, p < 0,05), i, naprotiv, uvelicheniya kontsentratsii aktivnykh form dannogo belka v kletkakh dostigali za schet vozdeystviya na kletki Nutlin-3a — ingibitora MDM2, osnovnogo negativnogo regulyatora r53. Ustanovleno, chto regulyatsiya kak minimum trekh markerov differentsirovki, SASP14, IVL (uvelicheniye ekspressii v 3,9 i 3,7 raza sootvetstvenno pri nokdaune p53, p < 0,05) i TGM1 (umen'sheniye ekspressii vdvoye pri nokdaune TR53 i uvelicheniye v 1,7 raza pri vozdeystvii na kletki Nutlin-3a, p < 0,05), v kletkakh HaCaT zavisit ot aktivnosti p53. Pri etom v otnoshenii ekspressii TGM1 i p53 otmechena pryamaya zavisimost', kotoraya, vozmozhno, realizuyetsya oposredovanno, cherez izmeneniye ekspressii DNp63. V to zhe vremya modulyatsiya aktivnosti p53 ne privodit k znachitel'nym izmeneniyam ekspressii tsitokeratinov.