scholarly journals Mutations in two neuroblastoma rat sarcoma oncogenes are associated with progression of haematologic malignancies in Nigeria

2021 ◽  
pp. 62-74
Author(s):  
Nneoma Confidence JeanStephanie Anyanwu ◽  
Ahmed Babangida Suleiman ◽  
Elijah Ekah Ella ◽  
Haruna Makanjuola Kazeem ◽  
Maryam Aminu
Keyword(s):  
Developing Countries ◽  
Blood Donors ◽  
Gene Mutations ◽  
Prognostic Indicator ◽  
Mutation Rates ◽  
Nras Mutation ◽  
Ras Genes ◽  
Study Participants ◽  
Synthetic Oligonucleotides ◽  
Haematologic Malignancies

Although mutation in the RAS genes has become important in the evaluation of haematologic malignancies worldwide, developing countries like Nigeria are yet to integrate it as a diagnostic tool and prognostic indicator for improved therapy. This study determined mutations in codons 12 and 13 of NRAS gene in blood donors and haematologic malignant individuals using multiplex (AS-PCR) and Sanger sequencing, thus highlighting the mutations as helpful diagnostic and prognostic tool. AS-PCR was used to selectively amplify mutation-specific synthetic oligonucleotides from the cfDNA of 100 study participants (50 cancer patients and 50 blood donors). Percentage mutation of 31.0% was seen in NRAS_G12D gene while NRAS_G13C had 17.0%. Twenty nine (29.0%) of the NRAS_G12D mutations were found in haematopoietic malignant patients and 2.0% were found in blood donors, while 15.0% of the NRAS_G13C were found in the malignant patients, confirming the occurrence of NRAS gene mutations in haematologic cancers and predominance of the G-A transition. The highest rate of mutation was observed in leukaemia patients, having a significant association with codon 13 (p = 0.042). Stages 3 and 2 cancers each had the highest mutation rates of NRAS_G12D and NRAS_G13C, revealing possible link between these mutations and susceptibility and progression of haematologic malignancies, which is higher in leukaemia. Further NRAS mutation studies and its role in other cancers are advocated, especially targeted towards ameliorating diagnosis and prognostic therapy. Challenges related to diagnosis and management of haematologic cancer continue to persist in developing countries like Nigeria. Thus, there is a need to go beyond studying the incidence and distribution pattern of these malignancies to capturing immunogenetic parameters of affected individuals.

The possible role of S gene mutations of hepatitis B virus in intrauterine transmission

2020 ◽  
Author(s):  
Jiaxin Wu ◽  
Yongliang Feng ◽  
Zhiqing Yang ◽  
Ruijun Zhang ◽  
Dandan Wang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Gene Mutations ◽  
Hbv Dna ◽  
Mutation Rates ◽  
Control Group ◽  
Intrauterine Transmission ◽  
S Gene ◽  
B Virus

Abstract Background: Many hepatitis B virus (HBV) substances could inevitably enter fetuses and occurred neonatal intrauterine transmission. HBV often occurs mutation, especially S gene, and may lead to different outcomes on intrauterine transmission. We explored the associations between HBV S gene mutations of hepatitis B surface antigen positive (HBsAg-positive) mothers and intrauterine transmission. Methods: A total of 399 HBsAg-positive mothers and neonates were recruited and their general demographic information was collected between June 2011 and July 2013. The mothers with HBV DNA levels ≥ 106 IU/ml were selected, 22 mothers whose neonates occurred HBV intrauterine transmission were in the HBV intrauterine transmission group (GT) and 22 mothers were randomly selected from the remaining controls were in the control group (GC). Maternal whole-genome HBV DNA was extracted, amplified, cloned, and sequenced. Obtained sequences were adjusted, genotyped, and analyzed for mutation rates. A case-control study was designed to analyze the relationship between mutations in the S gene of HBV and intrauterine transmission. Results: Fifty-five neonates were found to have experienced intrauterine transmission (13.78%). Genotype B (4.55%), genotype C (88.64%) and inter-genotype B/C (6.81%) were found in the 44 HBsAg-positive mothers. The mutation rates of the S gene, in both genotypes B (0.58% vs 1.41%, P = 0.040) and C (7.56% vs 14.71%, P＜0.001), were lower in group T than in group C. Missense substitutions such as L84I, P47S, K10Q, A41P, M133L, A60V, and I42T only existed in group C. The mutation rates of G73S, I126T, and I126S in group C were higher (P < 0.001, P < 0.001, P = 0.010). Deletions occurred in the S gene. The occurrence of intrauterine transmission with maternal mutation A90V was higher (P < 0.001). This may have increased the risk of neonatal HBsAg expression (P = 0.022). Conclusions: The HBV S gene mutations of HBsAg-positive mothers may reduce the occurrence of HBV intrauterine transmission. It is possible for HBsAg-positive mothers infected with A90V to develop HBV chronic infection and transmit it to the fetus during pregnancy, resulting in neonatal HBV infection.

scholarly journals Circulation of Toscana Virus in a Sample Population of Corsica, France

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 39
Author(s):  
Shirley Masse ◽  
Nazli Ayhan ◽  
Lisandru Capai ◽  
Rémi Charrel ◽  
Alessandra Falchi
Keyword(s):  
Blood Donors ◽  
Cross Sectional Study ◽  
P Value ◽  
Healthy Population ◽  
Sample Population ◽  
Surveillance Systems ◽  
Toscana Virus ◽  
Serum Samples ◽  
Cross Sectional ◽  
Study Participants

Sandfly-borne phleboviruses pathogenic to humans, such as Toscana virus (TOSV) and sandfly fever Sicilian virus (SFSV), are endemic in the Mediterranean region. In France, several autochthonous cases of TOSV infection have been described which cause either meningitis or encephalitis. The aim of the present study was to estimate the seroprevalence of TOSV and SFSV antibodies in a healthy population from Corsica. In this cross-sectional study, participants were enrolled from the medical staff at University of Corsica Pasquale Paoli (UCPP) and from general practitioners of the Corsican Sentinelles Network. The seroprevalence study was based on virus microneutralization (MN). A total of 240 patients were tested for TOSV and SFSV. Altogether, 54 serum samples were confirmed for TOSV infection (seroprevalence = 22.5%). None of the samples were positive for SFSV (0/240). The main place of residence was significantly associated with TOSV seropositivity (p-value = 0.005). The overall rate of TOSV antibody seroprevalence observed in our study suggests a more intense circulation of TOSV in Corsica, with a rate significantly higher than the 8.7% reported in Corsica in 2007 from blood donors. The absence of seropositivity to SFSV seems to confirm the low circulation of this virus in Corsica and in continental France. The increasing circulation of TOSV reported here should encourage the implementation of surveillance systems to control phlebovirus infection.

scholarly journals A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 147 ◽  
Author(s):  
Carlo Capalbo ◽  
Francesca Belardinilli ◽  
Domenico Raimondo ◽  
Edoardo Milanetti ◽  
Umberto Malapelle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Metastatic Colorectal Cancer ◽  
Gene Mutations ◽  
Bioinformatic Analysis ◽  
Genetic Alterations ◽  
Molecular Heterogeneity ◽  
Clinical Approach ◽  
First Line ◽  
Ras Genes

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Arielle Celeste Heeke ◽  
Joanne Xiu ◽  
Sandeep K. Reddy ◽  
Jiji Jiang ◽  
Hongkun Wang ◽  
...  
Keyword(s):  
Age Groups ◽  
Young Patients ◽  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Mutation Rates ◽  
Molecular Profile ◽  
Nras Mutation ◽  
Fragment Analysis ◽  
Disease Biology ◽  
Kaplan Meier

505 Background: The incidence of colorectal cancer (CRC) among young individuals is rising. The effect of an individual’s age on their tumor molecular profile is unknown. Methods: Molecular profiles of 4,821 tumors obtained from younger and older CRC patients (pts) were reviewed and correlated with pt outcome. Protein expression (IHC), gene amplification (ISH), sequencing (NGS and Sanger), and fragment analysis were performed. T and Fisher’s exact tests determined differences between age groups; Kaplan-Meier methodology estimated survival. Results: Tumors from 1,277 younger (median age 40; range 15-45 yr) and 3,544 older (72; 65-98) pts were studied. Most frequently mutated genes included TP53, APC, KRAS, PIK3CA, SMAD4, and BRCA1/2. Mutation rates for BRAF (14.4% vs. 4.8%, p < 0.001), APC (62% vs. 54%, p = 0.0034), FBXW7 (9.6% vs. 5.5%, p = 0.01), and KRAS (45% vs. 41%, p = 0.02) were higher in older pts; NRAS mutation rates (4.5% vs. 3.9%) were similar in both groups. Younger pts had higher overexpression rates of HER-2/neu (3.2% vs. 1.8%, p = 0.017) and MGMT (64% vs. 58%, p = 0.001). Microsatellite instability (MSI), determined by IHC (MLH1, MSH2, MLH6 and PMS2) and fragment analysis, was similar between cohorts (10.3% vs. 8.1%), but somatic MSI high (determined by concurrent BRAF mutation) was higher in older pts (6% vs. 0%, p < 0.0001). There was no difference in TS (37% vs. 34%), ERCC1 (25% vs. 26%) or TOPO1 (49% vs. 46%) expression between age groups. Older pts showed a trend toward higher PD-L1 expression (2.9% vs. 0.7%, p = 0.0512) but there was no difference in the frequency of PD-1 expression on tumor-infiltrating lymphocytes (39% vs. 43%). Outcome was evaluable for 82 pts (younger, 47; older, 35). Most pts received FOLFOX + Bev as first line Rx. Median OS was worse in younger pts (p = 0.03). Low ERCC1 expression was associated with prolonged survival in older (p < 0.01) but not in younger (p = 0.3) pts. There was no association between TOPO1 expression and OS (p = 0.8). Pts with low TS expression showed a trend toward longer OS (p = 0.08). Conclusions: Young pts with CRC may carry genetic alterations that are distinct from older pts. A better understanding of disease biology may help to identify therapeutic targets for younger pts.

Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 418-418
Author(s):  
Jingyuan Wang ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
Richard M. Goldberg ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Dna Damage Repair ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Mutation Rates ◽  
Aberrant Expression ◽  
Damage Repair

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p < .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p < .05). Significantly higher prevalence of TMB-high ( > 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p < .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p < .01)and RELA (29% vs 0%, p < .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.

scholarly journals Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum

2006 ◽  
Vol 52 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Doris Hendig ◽  
Veronika Schulz ◽  
Marius Arndt ◽  
Christiane Szliska ◽  
Knut Kleesiek ◽  
...  
Keyword(s):  
Blood Donors ◽  
Family Members ◽  
Gene Mutations ◽  
Pseudoxanthoma Elasticum ◽  
Elastic Fibers ◽  
Fetuin A ◽  
Cardiovascular Involvement ◽  
Abcc6 Gene ◽  
Sandwich Enzyme Immunoassay

Abstract Background: Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue affecting the skin, retina, and cardiovascular system and characterized by progressive calcification of abnormal and fragmented elastic fibers in the extracellular matrix. The aim of the present study was to investigate the association of fetuin-A, a major systemic inhibitor of calcification, with PXE. Methods: Fetuin-A was measured by quantitative sandwich enzyme immunoassay in sera from 110 German patients with PXE, 53 unaffected first-degree family members, and 80 healthy blood donors. We determined the distribution of the fetuin-A polymorphisms c.742C&gt;T (p.T248M) and c.766C&gt;G (p.T256S) in these same 3 groups. The occurrences of the frequent ABCC6 gene mutations c.3421C&gt;T (p.R1141X) and c.EX23_EX29del were also assessed. Results: Serum fetuin-A concentrations in male and female PXE patients were lower than in unaffected first-degree relatives and controls [mean (SD) concentrations, 0.55 (0.11) g/L in patients; 0.70 (0.23) g/L in relatives; and 0.80 (0.23) g/L in controls (P &lt;0.0001)]. Serum fetuin-A was higher in female PXE patients with cardiovascular involvement than in the corresponding male group (P &lt;0.05). The fetuin-A polymorphism frequencies did not differ among PXE patients, family members, and blood donors. Conclusion: A deficiency of multidrug resistance-associated protein 6 leads to alteration of circulating substrates, e.g., inhibitors of calcification as fetuin-A, leading to progressive mineralization of elastic fibers in PXE.

Hepatitis B virus subgenotype A1, occurrence of subgenotype D4, and S gene mutations among voluntary blood donors in Kenya

Virus Genes ◽  
2013 ◽  
Vol 47 (3) ◽  
pp. 448-455 ◽  
Author(s):  
Simeon Owuor Kwange ◽  
Nancy L. M. Budambula ◽  
Michael Kibet Kiptoo ◽  
Fredrick Okoth ◽  
Missiani Ochwoto ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Blood Donors ◽  
Gene Mutations ◽  
S Gene ◽  
B Virus

scholarly journals BRAF, C-KIT, and NRAS mutations correlated with different clinicopathological features: an analysis of 691 melanoma patients from a single center

2021 ◽  
Author(s):  
Min Ren ◽  
Jing Zhang ◽  
Yunyi Kong ◽  
Yong Chen ◽  
Qianming Bai ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Statistical Significance ◽  
Gene Mutations ◽  
Clinicopathological Features ◽  
Similar Distribution ◽  
Nras Mutation ◽  
Exon 2 ◽  
Kit Mutation ◽  
Metastatic Lesions ◽  
Melanoma Patients

Abstract Aims To analyze the prevalence and relevance of pathogenetic mutations in BRAF, C-KIT, and NRAS in Chinese melanoma patients to provide some potential reference for the targeted treatment in China. Methods We described the frequency and distribution of BRAF, NRAS, and C-KIT mutation in 691 melanoma patients, and analyze the statistical significance of different gene mutation with clinicopathological features. Results BRAF mutation was found in 166 patients (24.0%), and V600E was the prominent genetic alteration (87.3%). Statistical analysis showed that younger patients had a higher BRAF mutation rate than the older. Furthermore, the frequency of BRAF mutation in patients with extremity location, ALM type, thinner thickness and no ulceration was more likely to be lower. The rate of NRAS mutation was 12.6% (38/302), mainly involved codon 61 in exon 3 and codon 12 in exon 2. C-KIT mutation was detected in 65 patients (9.4%), and the most common sites of mutations was L576 in exon 11 (44.6%). Patients with NRAS or C-KIT mutation had higher Clark level and more likely to be located in extremity than those without mutation. The concordance of BRAF, NRAS, and C-KIT mutations between paired primary and metastatic lesions was 89.6% (60/67), and visceral metastases showed a highest similar distribution of gene mutations versus primary melanomas compared with lymph nodes and cutaneous metastases. Conclusions In this large cohort on Chinese population, the frequency of BRAF and NRAS mutation was relatively lower than that in Caucasian, but the clinicopathological features of BRAF, C-KIT and NRAS mutation were similar. Paired primary and metastatic lesions showed high concordance of gene mutations.

scholarly journals Issues of research ethics and clinical ethics in developing world, possible solution: a way forward

2012 ◽  
Vol 3 (3) ◽  
pp. 12-15
Author(s):  
Muhammad Waseem Khan ◽  
Imrana Niaz Sultana ◽  
Afrasiab Khan
Keyword(s):  
Developing Countries ◽  
Research Ethics ◽  
Medical Technology ◽  
Research Study ◽  
Developing World ◽  
Human Subjects ◽  
Research Subjects ◽  
Developed Country ◽  
Do No Harm ◽  
Study Participants

Research plays a pivotal role in the progress of inventions in medicines and medical technology. It is noticed that researchers from developing world or multinational companies are interested to conduct their research studies in developing countries, in doing so sometimes it is noticed that rather benefiting the participants it causes significant harm to the research study participants of developing countries. Ethical lapses in research can significantly harm human subjects. In research ethics the basic aim of ethics is distinguishing between right and wrong, to recognize the wrong doings and try to avoid them from harming research subjects in any research study whether that is done in developing country or developed country. It must follow the principle of non malefiecence or do no harm. DOI: http://dx.doi.org/10.3329/bioethics.v3i3.12559 Bangladesh Journal of Bioethics 2012; 3(3):12-15

Estimation of mutation rates based on the analysis of polypeptide constituents of cultured human lymphoblastoid cells.

Genetics ◽  
1988 ◽  
Vol 119 (3) ◽  
pp. 693-703
Author(s):  
E H Chu ◽  
M Boehnke ◽  
S M Hanash ◽  
R D Kuick ◽  
B J Lamb ◽  
...  
Keyword(s):  
Structural Gene ◽  
Somatic Mutations ◽  
Polyacrylamide Gel Electrophoresis ◽  
Gene Mutations ◽  
Apparent Molecular Weight ◽  
Cell Generation ◽  
Mutation Rates ◽  
Cell Clones ◽  
Protein Variants

Abstract A subclone of a human diploid lymphoblastoid cell line, TK-6, with consistently high cloning efficiency has been used to estimate the rates of somatic mutations on the basis of protein variation detected by two-dimensional polyacrylamide gel electrophoresis. A panel of 267 polypeptide spots per gel was screened, representing the products of approximately 263 unselected loci. The rate of human somatic mutation in vitro was estimated by measuring the proportion of protein variants among cell clones isolated at various times during continuous exponential growth of a TK-6 cell population. Three mutants of spontaneous origin were observed, giving an estimated spontaneous rate of 6 x 10(-8) electrophoretic mutations per allele per cell generation (i.e., 1.2 x 10(-7) per locus per cell generation). Following treatment of cells with N-ethyl-N-nitrosourea, a total of 74 confirmed variants at 54 loci were identified among 1143 clones analyzed (approximately 601,000 allele tests). The induced variants include 65 electromorphs which exhibit altered isoelectric charge and/or apparent molecular weight and nine nullimorphs for each of which a gene product was not detected at its usual location on the gel. The induced frequency for these 65 structural gene mutants is 1.1 x 10(-4) per allele. An excess of structural gene mutations at ten known polymorphic loci and repeat mutations at these and other loci suggest nonrandomness of mutation in human somatic cells. Nullimorphs occurring at three heterozygous loci in TK-6 cells may be caused by genetic processes other than structural gene mutation.

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