A Single Nucleotide Polymorphism in Pro-Apoptotique Protein BIM Affects Chronic Myeloid Leukaemia Evolution during Imatinib Treatment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4227-4227
Author(s):  
Vanessa Augis ◽  
Francis Belloc ◽  
Kelly Airiau ◽  
Claudine Chollet ◽  
Francois-Xavier Mahon

Abstract The tyrosin kinase inhibitor imatinib induces apoptosis in chronic myeloid leukaemia (CML) cells. RNA interference experiments have demonstrated that the pro-apoptotic protein BIM (Bcl-2 interacting mediator of cell death) was absolutely essential to this apoptosis. Thus, mutations in BIM sequence could lead to imatinib resistance independently of BCR-ABL mutations. In the current study, we performed BIM coding sequence analysis, using complementary DNA of leukocytes from CML patients mostly secondary resistant to imatinib. A total of 58 patients were analysed: secondary resistant to imatinib (n=40), or on the contrary sensitive to it (n=18). They were in chronic phase (CP, n=43), in accelerated phase (AP, n= 12), or in blastic phase (BP, n=3). Four patients were mutated in the tyrosin kinase domain of BCR-ABL. We did not find any mutation with amino acid change on the coding sequence of BIM. However, we observed a single nucleotide polymorphism (SNP) located in the fifth exon which encode for the BH3 alpha helix part of the protein. The impact of this previously described silent polymorphism C465T (rs724710) has never been studied before. We found the 3 following genotypes : C/C homozygous, T/T homozygous and T/C heterozygous. T/T genotype was the less frequent (It represents about 5% in the European population described in the international Hapmap project). Although not significant (10%, p=0.1468), we observed an increased T/T genotype frequency in the resistant population. In this resistant group, the T/T genotype frequency was increased in advanced phases (AP+BP, 20%) as compared to CP (4%, p=0.0016) or to sensitive cohort (5.6%, p=0.0153) (Fig.1). T/T genotype could affect RNA stability, translation speed and protein folding as described by Kimchi-Sarfaty et al. for the MDR1 gene (Science2007;315:525–8). This genotype can possibly be in linkage disequilibrium with others SNPs or abnormalities (i.e. in the promoter, in splicing sites) in the non coding sequence. The analysis of this polymorphism could be useful to predict the evolution of the disease during imatinib treatment and discriminate resistant patients particularly in advanced phase of the disease. Fig 1 : Genotypes distribution of the C465T polymorphism. Fig 1. Genotypes distribution of the C465T polymorphism. Fig 1. Genotypes distribution of the C465T polymorphism.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1683-1683
Author(s):  
Francois-Xavier Mahon ◽  
Vanessa Augis ◽  
Kelly Airiau ◽  
Marina Josselin ◽  
Beatrice Turc ◽  
...  

Abstract Abstract 1683 BIM is a pro-apoptotic protein essential to tyrosine kinase inhibitors (TKI) response in chronic myeloid leukaemia (CML) patients. Thus, mutations in BIM sequence could lead to imatinib resistance independently of BCR-ABL mutations. Recently, a deletion polymorphism in intron 2 of BIM was demonstrated to confer intrinsic TKI resistance in asiatic patients (Ng et al, nature medicine, 2012). However the Caucasian population is not concerned by this intronic deletion polymorphism. So, in the current study we performed BIM coding sequence analysis in 72 CML imatinib-treated patients and among them 40 were resistant to imatinib in our center from French population of patients. For twenty patients, the disease evolved in either acceleration or blastic phases at least once during the study. We did not find any mutation with amino-acid change in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP) c465C>T (rs724710) in the region coding for the active BH3 domain. A strong statistic link was found between the presence of the T allele of this polymorphism and the Sokal high risk group (p=0.0065). The frequency of the T allele was found higher in non responsive patients than in a local healthy donor reference population (p=0.0049). Similarly, the analysis showed an association of this T allele with the frequency of mutations on the tyrosine kinase domain of BCR-ABL (p<0.001) but not with additional chromosomal alterations. Moreover, the presence of the allele T significantly lengthened the time of achievement of major molecular remission. Finally, the presence of the T allele was found related to a decreased basal expression of the Bim mRNA in the circulating mononuclear cells of healthy donors. These results suggest that analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of CML patients under imatinib treatment. Disclosures: Mahon: Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.


Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 283 ◽  
Author(s):  
Laith N. AL-Eitan ◽  
Bashar H. Al-Ahmad ◽  
Fouad A. Almomani

Breast cancer (BC) pathogenesis is poorly understood and not yet completely determined. BC susceptibility genes are responsible for 20% to 25% of breast cancer risk. The main objective of this study is to identify the genetic polymorphisms within the Harvey rat sarcoma viral oncogene homolog (HRAS1) and interleukin-1 receptor antagonist (IL1-Ra) genes in Jordanian BC female patients and to investigate the genetic association of these polymorphisms with BC. Samples were collected from 150 Jordanian BC patients and 187 healthy age-matched controls. PCR and PCR-RFLP techniques were used to identify genetic polymorphisms within these candidate genes. The single nucleotide polymorphism single nucleotide polymorphism (SNP) association web tool SNPStats (v. 3.6) was used to investigate the allelic and genotypic association with BC. Different statistical analyses were used to study the correlation between the investigated genetic variants and several prognosis factors of BC. A genetic association between BC susceptibility and Il-1β rs1143634 was found specifically at the allelic level of E1 as a risk allele (72% in the cases vs. 64.2% in the controls). Another genetic association was found in the IL-Ra gene (86-VNTR (variable number tandem repeat)), which presented one repeat allele (24.1% in cases vs. 15.59% in controls) and could be considered as a risk allele in Jordanian women. In contrast, this study found that there is no genetic association between Il-1β SNP rs16944 and BC. In addition, a significant association was found between the allelic level of the HRAS1 gene and BC susceptibility. Since this study is the first to be conducted on the genetic susceptibility of these genes to BC in the Jordanian population, more investigations on the link between BC and these variants are recommended to determine the impact of these polymorphisms on other ethnic groups.


2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Abinaya Manivannan ◽  
Jin-Hee Kim ◽  
Eun-Young Yang ◽  
Yul-Kyun Ahn ◽  
Eun-Su Lee ◽  
...  

Pepper is an economically important horticultural plant that has been widely used for its pungency and spicy taste in worldwide cuisines. Therefore, the domestication of pepper has been carried out since antiquity. Owing to meet the growing demand for pepper with high quality, organoleptic property, nutraceutical contents, and disease tolerance, genomics assisted breeding techniques can be incorporated to develop novel pepper varieties with desired traits. The application of next-generation sequencing (NGS) approaches has reformed the plant breeding technology especially in the area of molecular marker assisted breeding. The availability of genomic information aids in the deeper understanding of several molecular mechanisms behind the vital physiological processes. In addition, the NGS methods facilitate the genome-wide discovery of DNA based markers linked to key genes involved in important biological phenomenon. Among the molecular markers, single nucleotide polymorphism (SNP) indulges various benefits in comparison with other existing DNA based markers. The present review concentrates on the impact of NGS approaches in the discovery of useful SNP markers associated with pungency and disease resistance in pepper. The information provided in the current endeavor can be utilized for the betterment of pepper breeding in future.


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