Sailaja Kagita1, Sadasivudu Gundeti2, Raghunadharao Digumarti1
1Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, Andhra Pradesh, India.
2Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India.
DOI: 10.4103/jnsbm.JNSBM_194_17
ABSTRACT
Background: Imatinib (IM) results in durable responses in a large number of patients with chronic myeloid leukemia (CML). However, a substantial number develops drug resistance. There could be several reasons for the heterogeneity of response. To survive genotoxic damage induced by IM, BCR-ABL1 can modulate DNA repair mechanisms, cell-cycle checkpoints, and Bcl-2 family members. Hence, we aimed to find out the impact of single-nucleotide polymorphisms mainly TP53Arg72Pro, excision repair cross-complementing protein 1 (ERCC1) Asn118Asn (C118T) and deletion in intron 2 of BIM genes in CML patients and their association with disease progression and treatment outcome. Materials and Methods: In the present study, 174 CML and 174 control samples were analyzed for polymorphisms of TP53Arg72Pro, ERCC1 C118T, and intron 2 deletion in BIM genes using polymerase chain reaction-restriction fragment length polymorphism method. Results: Genotyping of TP53Arg72Pro polymorphism showed a trend toward proline genotype/allele association with younger age (P = 0.031), advanced phase, high BCR-ABL1 expression levels and presence of tyrosine kinase domain (TKD) mutations compared to respective groups. Genotyping of ERCC1 C118T polymorphism showed a significant association of CT genotype and T allele with high BCR-ABL1 levels BIM deletion polymorphism was not observed in the present study (P = 0.030) and presence of TKD mutations (P = 0.013). The 72 proline allele and heterozygous 118CT genotype frequencies were significantly elevated in deceased patients compared to those on IM and other tyrosine kinase inhibitors treatment. Conclusion: our data suggested that proline genotype/allele of TP53Arg72Pro polymorphism possibly leading to inefficient apoptosis and 118CT genotype in ERCC1 gene with possibly less DNA repair efficiency might be responsible for the suboptimal responses to IM and poor survival in CML patients. Deletion in intron 2 of BIM gene was not observed in our study.
Keywords: BIM, Chronic myeloid leukemia, ERCC1, Imatinib, Polymorphism, TP53.
