MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer.

Absarul Haque,Abdul Wahab Noor Wali,Khalid Hussain Wali Sait,Qamre Alam,Mahmood Rasool,Mohammad Zubair Alam,Nisreen Anfinan

doi:10.3389/fgene.2020.00516

Absarul Haque, Abdul Wahab Noor Wali + Show 5 more

Open Access

https://doi.org/10.3389/fgene.2020.00516

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Abstract

In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy.

Highlights

Ovarian cancer (OC) represents the fifth leading cause of death among women, but ranked number one in deaths due to gynecological malignancies (Cancer Facts and Figures, 2018; Torre et al, 2018)
Among single nucleotide polymorphisms (SNPs) reported in the MDR1 gene, three insertion/deletion SNPs, C1236T in exon 12, G2677T/A in exon 21 and C3435T located in exon 26 respectively, have been most widely investigated and were determined to be functionally significant and ethnically found to be different when mapped at this region of gene (Kelland, 2007; Sharom, 2008; Miyata et al, 2016)
Knowing the important role of MDR1 in predicting treatment response with chemotherapeutic drugs, we evaluated the SNPs variants in C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26, and compared its association on mRNA expressions in tumor tissues in order to establish their relevance in terms of the response to chemotherapy and prognosis in Saudi ovarian cancer women

Summary

Introduction

Ovarian cancer (OC) represents the fifth leading cause of death among women, but ranked number one in deaths due to gynecological malignancies (Cancer Facts and Figures, 2018; Torre et al, 2018). Multiple mutational analysis revealed that MDR1 is genetically quite variable, suggesting that single nucleotide polymorphisms (SNPs), may have significant effects on the expression and function of P-gp transporter (Potocnik et al, 2001; Meissner et al, 2004; Sakaeda et al, 2004; Li et al, 2006; Potocnik et al, 2008) In this effort, many researchers have analyzed that the SNPs within the gene of the MDR1/P-gp transporter, have established a relationship with variation in expression and function of MDR1, which eventually lead to the affect responsiveness to drugs, along with susceptibility to disease (Kelland, 2007; Sharom, 2008; Tsai et al, 2015). Further determination of genetic variations in MDR1 gene in a particular population may be vital for individualized pharmacotherapy

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